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J Virol. Aug 2008; 82(15): 7252–7263.
Published online Apr 2, 2008. doi:  10.1128/JVI.00104-08
PMCID: PMC2493305

Intrinsic Structural Disorder in Adenovirus E1A: a Viral Molecular Hub Linking Multiple Diverse Processes[down-pointing small open triangle]

Viruses are obligate intracellular parasites. Their genomes are not large enough to encode all the functions required to independently produce progeny; hence, viruses are absolutely dependent on host cell functions. Mechanistically, these host cell processes in eukaryotes are founded on an exquisitely complex series of molecular interactions. In particular, the execution of complex biological processes requires the precise interaction and regulation of thousands of proteins. The definition of cellular interactomes by systematic analysis of protein-protein interactions has revealed complex molecular networks (39, 82, 111, 122). Most cellular proteins interact with only one or two other proteins, making only one or two connections. However, the minority of proteins interact with tens, or even hundreds, of other proteins to form network hubs. Hub proteins play key roles in regulating and orchestrating the activity of the proteins they interact with, effectively creating functional modules within the cellular interactome (35, 48, 62).

The central role served by cellular hub proteins in regulating cell functions makes them ideal targets during a viral infection. By targeting a single cellular hub, a viral regulatory protein can effectively gain control over an entire module, potentially comprised of hundreds of proteins. By targeting multiple cellular hubs, a virally encoded hub can transform the architecture of the cellular protein interaction network, reprogramming virtually all aspects of cell function and behavior.

The viral oncogenes of the small DNA tumor viruses encode some of the most versatile and potent viral hub proteins. Among these, adenovirus E1A is one of the best characterized and is the subject of this review.


Hub proteins interact with large numbers of structurally diverse targets, defining the architecture of protein interaction networks (48). Historically, protein-protein interactions are associated with globular protein domains with a fixed three-dimensional structure that forms a specific high-affinity interaction with its targets. The high level of connectivity observed with hub proteins is not compatible with these characteristics, as the interaction potential of such a protein is limited to its static solvent-accessible surface. More recently, it has been recognized that proteins can be entirely unstructured or can contain disordered regions interspersed with independently folded globular domains (26). Intrinsically disordered proteins or regions, which are defined as those lacking a well-structured three-dimensional fold, exist in a dynamic and flexible state that is largely free of secondary structural elements and tertiary interactions. In this way, thermal motion allows the segments to spatially sample conformational space for appropriate molecular contacts. In addition, it is well recognized that protein-protein interactions can be mediated by short segments of linear sequence, referred to as molecular recognition features (MoRFs) or linear motifs (LMs), which are often characterized by local structural plasticity or disorder (25). Thus, the incorporation of local or extended regions of intrinsic disorder allows hub proteins to adopt multiple conformations, allowing “promiscuous” binding to diverse partners and maximizing their interaction capabilities (25). Intrinsically disordered proteins are not necessarily completely disordered. The CBP coactivator/acetyltransferase is a prime example, as it contains multiple ordered domains linked by stretches of local disorder (26).

As a consequence of protein-protein interaction, a formerly unstructured region becomes locked into a static conformation. A MoRF that adopts an α-helical, β-strand, or irregular conformation upon binding is termed an α-MoRF, β-MoRF, or I-MoRF, respectively (88). Binding is accompanied by a large decrease in conformational entropy, which uncouples specificity from binding strength. This uncoupling effectively makes highly specific interactions readily reversible, which is ideal for signal transduction proteins that must not only associate specifically to initiate a signal but also dissociate when signaling is complete. Bioinformatics studies suggest that intrinsic disorder is highly prevalent in eukaryotic proteins. Indeed, >70% of signaling proteins are predicted to have extended regions of disorder (57).


The small DNA tumor viruses, such as adenovirus, papillomavirus, and polyomavirus, all induce cancers in animal or human systems (99). Oncogenic transformation directly reflects the fundamental changes these viruses effect on the cellular protein interaction network. Each of these viruses expresses multifunctional viral hub proteins that deregulate cell growth by interaction with multiple cellular proteins (99). This review focuses on the human adenovirus (HAdV) early region 1A (E1A) proteins, although there are many commonalities between its functions and those of the polyomavirus large T antigen and papillomavirus E7 proteins.

E1A is the leftmost adenoviral gene, and it has been most extensively characterized for HAdV serotype 5 (HAdV-5). The HAdV-5 E1A gene encodes two major proteins of 289 and 243 residues that are expressed at high levels early after infection. These proteins arise from differential splicing of the same transcript and differ only by the presence of an internal sequence of 46 amino acids in the larger protein (Fig. (Fig.1).1). These E1A proteins are localized in both the cytoplasm and nucleus (110, 128). Three additional mRNA species that encode proteins of 217, 171, and 55 amino acids are produced at later times (123, 129). Splicing maintains the same translational reading frame for all E1A products except the 55-residue product, which has only 28 amino acids in common with the other E1A products. During infection, splice site selection initially favors production of the 289- and 243-residue proteins, but it shifts to favor the 55-residue product at later times (120). Sequence comparisons of the largest E1A proteins of several adenovirus serotypes identified four regions of sequence similarity, designated conserved region 1 (CR1), CR2, CR3, and CR4 (4, 5, 66, 131) (Fig. (Fig.11).

FIG. 1.
Map of E1A, CRs, and location of selected MoRFs. The primary HAdV-5 E1A RNA transcript is alternatively spliced to yield two major mRNA-encoding proteins of 289 and 243 residues (R). Comparative analysis of the sequences of the E1A proteins from different ...

In infected human cells, E1A is essential for a productive viral infection (64). The effects of E1A can be considered to be largely, if not completely, mediated by changes in transcription. E1A is the first viral gene expressed after infection (98) and is responsible for activating viral gene transcription. It also reprograms host cell gene expression, forcing quiescent cells to enter and pass through the cell cycle, blocking cell differentiation (7, 8, 34, 38). E1A also plays a role in suppressing the inflammatory response to the viral infection (113). HAdV infection of human cells is lytic, usually resulting in the death of the host cell and the release of progeny virus.

In contrast to that of human cells, HAdV infection of rodent cells is nonproductive and does not result in cell death. The oncogenic properties of E1A in rodent cells are readily apparent (94). E1A can efficiently immortalize rodent cells or fully transform them in cooperation with a second oncogene, such as the adenovirus E1B gene or activated ras (7, 38, 116). Despite the clear oncogenic properties of E1A, its expression in previously transformed human and animal cells has shown that it can also function as an anti-oncogene to suppress metastasis, angiogenesis, and tumorigenicity in vivo, trigger apoptosis, and induce differentiation to an epithelium-like cell type (21, 36, 94).

The multiple activities of E1A in different experimental systems reflect its role as a viral molecular hub. E1A makes many independent connections to the cellular protein interaction network, and many of its targets are hub proteins themselves. At present, there are about 50 distinct protein targets that have been reported to interact with E1A. Mechanistically, E1A alters or inhibits the normal function of these cellular proteins and may even establish new connections in the cellular network. Thus, E1A effectively rewires the infected cell to create an environment that is more conducive to viral replication.


There is no atomic structure available for any of the E1A proteins, but there are anecdotal reports of attempts to determine it. This is suggestive, but not conclusive, evidence that E1A may be highly disordered, as the structural flexibility of disordered regions makes it impossible to determine a high-resolution protein structure by X-ray crystallography and/or nuclear magnetic resonance. E1A has no known cellular orthologs, but CR1 and CR2 share sequence similarity with portions of polyomavirus large T antigen and papillomavirus E7 (33, 104, 133). A recent study describing the solution structure of human papillomavirus 45 E7 reported that the CR1 and CR2 portions of E7 are intrinsically disordered (101), suggesting that the corresponding regions of E1A are similarly disordered. Extensive mutation analysis has shown that E1A is highly modular and that insertions or deletions generally interfere only with specific subsets of function and do not globally affect activity (7). The observation that recombinant E1A that had been fully denatured by boiling still retained the ability to induce transcription and translocate to the nucleus when microinjected into cells further supports the notion that E1A is largely unstructured (68).

Although the reliable prediction of the three-dimensional structure of a globular protein from primary amino acid sequence alone is not yet a reality, identification of sequences likely to be intrinsically disordered is now considered routine. Bioinformatic analysis using PONDR (109), Foldindex (130), and DISOPRED (138) suggest that the largest E1A proteins of HAdV-3, -4, -5, -9, -12, and -40, which represent each of the six HAdV subgroups, exist largely in a natively unfolded conformation. Indeed, the only portions of these E1A proteins generally predicted to have any native structure are a small N-terminal region and CR3 (Fig. (Fig.22).

FIG. 2.
Alignment of selected HAdV E1A proteins and prediction of intrinsic disorder. The amino acid sequences of the largest E1A proteins of HAdV-3, -4, -5, -9, -12, and -40, which represent each of the six HAdV subgroups, are shaded with respect to their predicted ...


Our current understanding of E1A is that it consists of a collection of independent protein binding motifs, or MoRFs, that allow it to interact with a plethora of cellular targets. As described earlier, these MoRFs are unlikely to exhibit a specific structure until they are in contact with their protein targets. Presumably, these interaction motifs have evolved independently to mimic cellular protein interaction surfaces to provide an advantage to the virus. The organization of E1A into discrete protein interaction modules makes it ideally suited for mutational analysis (7). It should be noted that although the various E1A domains can function independently, it is likely that some activities of E1A result from a coordination of activities localized to separate domains that will occur only in a cis, rather than a trans, fashion (137). For example, E1A can serve as a scaffold by binding an enzyme using one domain and a possible substrate using another to facilitate covalent modification (14, 150).

The identification of the protein interaction motifs within E1A and the determination of the specific residues involved in intermolecular contacts are valuable areas of investigation that have enriched our understanding of eukaryotic protein function. For example, E1A interacts with the cellular transcriptional corepressor C-terminal binding protein (CtBP) via the short motif PXDLS (where X is variable), which was later identified in various cellular repressor proteins (16). Similarly, the interaction of E1A with the cell cycle regulator pRb requires the core motif LXCXE (93), the interaction with the BS69 corepressor requires the motif PXLXP (2), and the interaction with CBP/p300 requires the motif FXD/EXXXL (100). Each of these sequences was originally identified within HAdV E1A but has since been found in numerous other proteins that interact with these targets (Fig. (Fig.1).1). Thus, the identification and characterization of MoRFs within E1A allow them to be subsequently detected in the primary sequences of other proteins, and this detection immediately suggests pertinent information regarding their cellular activities and mechanism of action. We exploited this approach to map a corepressor-nuclear receptor (“CoRNR”) box motif (55, 103) in E1A (LXXLIXXXL) (Fig. (Fig.1)1) that confers binding to the thyroid hormone receptor (TR), and this enabled us to identify a new transcriptional activation function in a cellular protein containing this motif (84).

A brief description of the currently identified MoRFs, their cellular targets, and their role in E1A function follows below. For convenience, the MoRFs are organized based on their location within E1A, and the approximate positions for selected MoRFs are shown in Fig. Fig.11.

N terminus/CR1.

The N terminus of E1A, which corresponds to the first 41 residues of HAdV-5 E1A, binds a wide range of cellular targets (4). To date, at least 15 different proteins have been confirmed to bind to this short amino acid sequence. The majority of these consist of proteins that directly regulate gene expression. These include specific transcriptional regulators, such as AP-2 (118), myogenin (127), and TR (85, 135), or more general transcriptional coactivators, such as p300/CBP (3, 27), p400 (37), transformation/transcription domain-associated protein (TRRAP) (19), pCAF (108), and TATA box binding protein (TBP) (75, 119). Additional proteins that bind to this region include the receptor for activated protein kinase C (RACK1) (112), the Ran GTPase (20), the S4 and S8 components of the 19S regulatory components of the proteasome (46, 128), the RIIα subunit of protein kinase A, and the recently reported Nek9 kinase related to the NimA (never in mitosis gene A) family of mitotic kinases (102). The large repertoire of targets for the N terminus of E1A reflects its heterogeneity of function. This region of E1A is involved in transformation, suppression of differentiation, induction of DNA synthesis and cell cycle progression, and modulation of gene expression, either as a transactivator or a repressor (7, 8, 34, 38).

The N termini of the different HAdV E1A proteins are typically predicted by bioinformatics tools to contain a mixture of structured and unstructured regions. However, the N terminus of HAdV-5 E1A differs from the others, as it is predicted to be primarily structured (Fig. (Fig.2).2). Several groups have individually mutated each of the first 30 N-terminal residues of HAdV-5 E1A and assessed these mutants for their ability to bind various cellular proteins and perform a variety of functions (10, 106). From these analyses, it is clear that while most residues are preferentially involved in binding to one or two targets, L19, L20, and L23 are important for interaction with many different targets, suggesting that they may be structurally important.

The N-terminal regions of HAdV E1A proteins are typically predicted to contain an α-helix (4, 40). In HAdV-5, a portion of this putative helix spanning residues 16 to 28 has amphipathic characteristics (Fig. (Fig.3).3). A similar amphipathic α-helix is also predicted between residues 10 and 27 of HAdV-12 E1A. Several lines of evidence support the existence of these putative amphipathic α-helices. First, HAdV-5 E1A interacts with the unliganded TR via a CoRNR box motif (LXXL/I/HIXXXL/I) spanning residues 20 to 28 (84). The CoRNR box motif is also found in nuclear hormone corepressors, such as nuclear receptor corepressor splice variant (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) (Fig. (Fig.1),1), and forms an extended amphipathic helix that contacts a hydrophobic pocket on the unliganded nuclear hormone receptors (55, 103, 144). As a second line of evidence, the N terminus of HAdV-12 E1A interacts with the RIIα regulatory subunits of protein kinase A, functioning as a viral A kinase anchoring protein (AKAP) (31). It is well established that cellular AKAPs use an amphipathic α-helix of 14 to 18 residues to engage a preformed shallow groove on the surface of dimerized RIIα (13, 44), and the addition of such a peptide derived from a cellular AKAP blocks the interaction of HAdV-12 E1A with RIIα. The contribution of this putative helix for interaction with other targets remains to be determined. It is interesting that a simple amphipathic α-helix can be utilized to confer promiscuous interaction with diverse targets.

FIG. 3.
Helical wheel representation of a portion of the N terminus of HAdV-5 E1A. The sequence of HAdV-5 E1A from residues 16 to 28 may form an amphipathic α-helix. (A) Helix viewed from the side. (B) View of helix rotated 180° along the long ...

CR1 of E1A spans residues 42 to 72 in HAdV-5 E1A (4) (Fig. (Fig.2)2) and cooperates with the N terminus in binding several transcriptional regulators, including p300/CBP (28, 143). CR1 also has a critical role in releasing E2Fs that are associated with the pRb family of proteins (30, 58). Unhindered by pRb, free E2Fs activate transcription from viral early genes and cellular S phase-specific genes. E1A CR1, together with the N terminus, possesses a strong transcriptional activation activity, which is revealed when it is tethered to a promoter via a heterologous DNA binding domain (9). Like the N terminus, this region is largely unstructured. Recently, a structure of a short fragment of HAdV-5 E1A CR1 was resolved in association with the E2F binding region of pRb (78). That work identified an α-MoRF of the sequence LXE/DLY spanning residues 43 to 47 in HAdV-5 E1A, which is found in other viral and cellular proteins that also bind pRb (Fig. (Fig.1).1). E1A CR1 directly competes for the same interactions as E2F and is thus capable of preventing E2F from binding to pRb. Interestingly, the authors of the study observed an increase in ordering of the pRb L1 loop (between helices α4 and α5 of pRb) upon E1A binding, which is a classic feature of the high-specificity but low-affinity interactions observed with inherently unstructured proteins (78). This change in structure is likely concurrent with structural changes in the E1A CR1 region upon binding. The dissociation constant for this interaction is relatively high (~1 μM) and is 1,000-fold higher than what is observed for CR2 and pRb interaction (~1 nM; see below) (78). The current model for the effects of E1A on pRb function is described further in the CR2 section below.

Recently, a MoRF conferring interaction with TRRAP was identified in nuclear protein mapped to the AT locus (NPAT), which was also proposed to exist in E1A (22). This putative MoRF is comprised of the core sequence E/DLY/FD (residues 45 to 48 in HAdV-5 E1A) and partially overlaps the pRb binding MoRF described above. This region of E1A is required for interaction with TRRAP (19), but specific point mutations in this motif have not yet been tested for their effect on E1A-TRRAP interaction.

CR1 is also required for interaction with the CH3 region of p300/CBP via the MoRF FXDXXXL (residues 66 to 72 in HAdV-5 E1A), which is also found in a number of other viral and cellular proteins that bind p300/CBP (100) (Fig. (Fig.1).1). This region of E1A along with the N terminus is required to form an interaction with p300/CBP in vivo (28, 121). It seems likely that E1A uses multiple MoRFs that confer highly specific but low-affinity interactions with target proteins, such as p300, in order to form a stable high-affinity interaction.


CR2 is required for a number of E1A functions that are important for virus replication; these include activation of viral early gene expression and stimulation of the infected cell to enter the cell cycle (7, 8, 34, 38). In addition, CR2 is required for oncogenic transformation of primary rodent cells in culture (61, 69, 73, 92, 115, 132, 142), stabilization of p53 (147), induction of apoptosis (95), and sensitization of cells to the cytotoxic effects of tumor necrosis factor (117). The CR2 regions of the different E1A proteins are predicted to lack a defined structure, with the notable exception of HAdV-12 E1A (Fig. (Fig.2),2), and can bind multiple proteins via short MoRFs (Fig. (Fig.1).1). In HAdV-5 E1A, CR2 spans residues 115 to 137 (4). The remainder of this section will discuss what is known about the interaction between E1A CR2 and its four known targets: pRb and its family members, BS69, UBC9, and the S2 subunit of the 19S regulatory complex of the proteasome.

Notably, the first E1A-interacting protein to be identified was the retinoblastoma susceptibility protein pRb (141). This interaction, which is absolutely required for E1A to cooperatively transform primary rodent cells in culture, was also the first demonstration of a tumor suppressor physically interacting with an oncogene. E1A interacts specifically with hypophosphorylated active pRb mainly through the LXCXE motif spanning residues 122 to 126 within CR2 of HAdV-5 E1A (58, 87). This motif was subsequently identified for other viral and cellular proteins that also interact with pRb (Fig. (Fig.1)1) and is present in all currently sequenced human and simian AdV E1A proteins (4). Although no structural data are available for this portion of E1A, the crystal structure of a short peptide containing the LXCXE motif from human papillomavirus type 16 (HPV16) E7 (residues 22-DLYCYEQLN-28) complexed with pRb indicates that it most likely forms an extended β-strand-like conformation that binds a shallow groove on the B-box of pRb (72). Thus, the LXCXE region can be considered a β-MoRF. The alternating residues (L, C, and E) point into the groove and make strong intermolecular contacts. Although the other residues in the motif do not interact with pRb, they do make intramolecular contacts that stabilize the conformation of the peptide in the bound state. This partially explains the observation that high-affinity interaction of LXCXE-containing proteins with pRb requires the presence of a preceding aspartic acid residue (51), which forms an H-bond with the second tyrosine (72). Notably, all human and simian AdV E1A proteins contain the preceding aspartic acid residue, and most contain a tyrosine at the position of the second X and are thus predicted to make high-affinity interactions with pRb (4).

The crystal structure of the E7 peptide shows that L28 also points into the groove and makes a hydrophobic contact with pRb similar to that made by L22. In HAdV-5 E1A, the corresponding amino acid is G128, but the following amino acid, F129, is postulated to make a contact similar to that of L28 in HPV16 E7. F129 is highly conserved in other HAdV and simian AdV E1A proteins (4). In addition, a patch of acidic residues downstream of the LXCXE motif is required to further stabilize the E7-pRb interaction. Studies have shown that this acidic patch contacts a patch of basic residues in pRb. Mutating these acidic residues to basic residues greatly reduces HPV E7 interaction with pRb, as does mutation of the basic residues in pRb to acidic residues (23). In a remarkable example of parallel evolution, a highly conserved acidic patch is present following the LXCXE motif in all HAdV and simian AdV E1A proteins (e.g., 133-DDEDEE-138 in HAdV-5 E1A) and the large T antigen of simian virus 40. Some reports indicate that mutation of these acidic residues also reduces the interaction of HAdV-5 E1A with pRb or the ability to overcome a pRb-dependent cell cycle arrest (1, 6). Interestingly, the HAdV-12 LXCXE motif differs from the other serotypes, as it is predicted to be structured, and this is a property shared with the E1A proteins of the other subgroup A viruses, HAdV-18 and -31 (Fig. (Fig.2,2, data not shown). It may therefore form a more stable complex with pRb, which could be related in part to the ability of the highly oncogenic subgroup A HAdVs to induce tumors in rodents.

The high-affinity interaction of CR2 with pRb essentially increases the local pRb concentration, allowing the lower-affinity pRb binding motif in CR1 (described above) to bind and dissociate it from transcription factors of the E2F family (78). This dissociation frees E2F to activate early viral transcription and also causes the infected cell to enter the cell cycle. This has been reviewed extensively elsewhere (32).

Another cellular protein that interacts with E1A through CR2 is BS69. Interaction with BS69 inhibits transcriptional activation by E1A CR3 and stabilizes E1A by blocking ubiquitination (59). BS69 is a transcriptional repressor that was originally identified as an E1A-interacting protein (49). It functions by recruiting corepressors, such as NCoR, and chromatin remodeling machinery, such as HDAC1, BRG1, and EZH2. A MYND domain mediates the interaction between BS69 and an MPXLXP motif spanning residues 112 to 117 in HAdV-5 E1A CR2 and other viral and cellular proteins (2) (Fig. (Fig.1).1). This PXLXP motif is not highly conserved and is observed only in the E1A proteins of subgroups C (HAdV-1, -2, -5, and -6) and A (HAdV-12, -18, and -31) (4). Interaction of E1A with BS69 has been reported to also require CR3, as the 243R product binds weakly compared to the 289R E1A (49), but this requirement has not been reproduced in another study (2). However, only the 289R E1A protein is able to relieve BS69-mediated repression of the transcriptional activator c-Myb (70). Although the exact consequences of the interaction of BS69 with E1A are not entirely understood, it is becoming clear that BS69 plays roles in cell cycle regulation and senescence (56, 136, 146).

A third target of CR2 is the small ubiquitin-like moeity (SUMO) conjugase UBC9 (ubiquitin conjugase 9). Like BS69, UBC9 was also first cloned and identified as an E1A binding protein (50). Interestingly, the binding site for UBC9 overlaps the LXCXE pRb binding motif, as the L122I E1A mutant no longer binds UBC9. However, the binding site is clearly different, as a C124G/E135K double mutant in the LXCXE motif, which cannot bind pRb, still interacts with UBC9 (50). Little is known about the consequence of E1A interaction with UBC9. The importance of the SUMO pathway in regulating virtually all aspects of cell function has been clearly established over the last few years (63), and it is likely that E1A modulates SUMOylation through interaction with UBC9. Interestingly, many E1A-interacting proteins are known to be SUMOylated, including p300/CBP, pRb, and CtBP (43, 65, 71).

The final target of CR2 is the S2 component of the 19S regulatory complex of the 26S proteasome (147). The S2 binding site also overlaps the pRb binding region in CR2, as deletion of residues 124 to 127 abrogates this interaction, although mutation of any individual residue in the LXCXE motif does not disrupt binding. The interaction of E1A with S2 interferes with proteasomal activity, contributing to the stabilization of p53 by E1A and the sensitization of cells to tumor necrosis factor alpha-induced apoptosis (147).

In summary, it is remarkable that the short, 23-amino-acid stretch which CR2 comprises mediates the interaction with four different proteins. This density of protein interaction motifs exemplifies the compact multifunctional nature of HAdV5 E1A and probably could not be achieved with a polypeptide chain with a fixed structure.


E1A CR3 encodes a C4 zinc finger (18) and functions as a potent transcriptional activation domain that is critical for activating viral early gene expression (7, 8, 34, 38). CR3 is sufficient alone to potently activate transcription when tethered to DNA as a fusion to a heterologous DNA binding domain (74, 81). The cores of CR3 from the six representative HAdV E1A proteins are predicted to have a defined structure (Fig. (Fig.2).2). Virtually all deletion mutants within CR3, unlike other regions of E1A, simply do not activate transcription (29, 60), and no MoRFs have been identified within this region. Taken together, these findings reinforce the concept that CR3 is a more-ordered region of E1A and that this structure is a requisite to activate transcription. As a result, the current model of CR3 function was built from painstaking analysis of point mutants. Indeed, every residue of HAdV-5 CR3 has been mutated to at least a conservative amino acid and assayed for transcriptional activation (42). This massive effort defined the factors and the key interaction residues of CR3 that are required to activate transcription of the early viral genes and generated a model that serves as the paradigm for nonacidic viral transcriptional activators. However, a three-dimensional structure has yet to be defined for this region.

In HAdV-5 E1A, CR3 spans residues 144 to 191 (4) and can be considered to be comprised of three functional subdomains: an N-terminal zinc binding region mapping between residues 139 and 179, a C-terminal promoter targeting a region spanning residues 183 to 188, and an acidic region that extends beyond CR3 that spans residues 189 to 200, termed auxiliary region 1 (AR1) (Fig. (Fig.4).4). Deletion of the entire C4 zinc binding subdomain, or any portion of it, results in a complete loss of transcriptional activation function. However, mutation of the promoter-targeting domain leads to a dominant-negative phenotype (139). The latter class of mutants continue to bind to limiting cellular factors through the zinc finger subdomain but are unable to associate with a promoter, resulting in squelching of the cellular factors and a loss of activation by wild-type E1A. Deletion of AR1, or a decrease in its overall acidic charge, also results in a loss of transcriptional activation (124).

FIG. 4.
The current model of E1A CR3-dependent activation of transcription. Top, linear representation of 289R E1A. CRs are labeled, and AR1 is denoted in yellow. Bottom, residues of E1A CR3 from 139 to 200 are indicated using a one-letter code. The coordinating ...

The zinc finger subdomain of CR3 interacts with cellular TBP (42) and with MED23, a component of the mediator adaptor complex (12), in order to nucleate the transcriptional preinitiation complex. These two targets interact with specific residues found within the zinc finger subdomain (139) (Fig. (Fig.4).4). Furthermore, these interactions require specific zinc coordination, as a single point mutant that converts the zinc finger to a C2H2 type results in a complete loss of transcription activation (140).

E1A has no specific DNA binding activity and is recruited to viral and cellular promoters via interaction between the promoter-targeting subdomain spanning residues 183 to 188 of HAdV-5 E1A and cellular sequence-specific DNA binding transcription factors (76). The adenoviral early region promoters contain binding sites for many cellular transcription factors that interact with this short region of CR3, including those of the cyclic AMP response element/activating transcription factor (ATF) family, upstream stimulatory transcription factor (USF), and Sp1 (76, 77). This region has also been shown to bind TBP-associated factor II 250 (TAFII250) and TAFII135 (41, 83). Interestingly, the promoter-targeting region in E1A is predicted to be unstructured (Fig. (Fig.2).2). This may contribute to its ability to interact with multiple unrelated transcription factors.

More recently, components of both major subunits of the proteasome were shown to interact with CR3 of the E1A proteins of each of the six HAdV subgroups (107). The S8 component of the 19S ATPase proteins independent of 20S (APIS) complex interacts with HAdV-5 E1A CR3 via residues 169 to 188. The addition of small amounts of exogenous S8 increases CR3 activity, whereas high levels abrogate transcriptional activation, suggesting that S8 is required in stoichiometric amounts for function. Moreover, small interfering RNA knockdown of S8 results in a loss of CR3-dependent transcriptional activation at levels similar to those seen with small interfering RNA knockdown of other targets of CR3, such as TBP. The 20S proteasome subunit has also been shown to interact with CR3 independently of APIS and the 26S proteasome via HAdV-5 E1A residues 161 to 177 (107). Chromatin immunoprecipitation experiments show that these components and E1A are found at both promoter and transcribed sequences, suggesting a role in both initiation and elongation. Chemical inhibition of the proteasome also represses CR3-dependent activation of transcription. These findings suggest that the proteasome directly controls E1A-dependent transcriptional activation. Moreover, mutational analysis has also established that the potency of E1A activation is inversely related to its stability (107), as has been observed for other transcriptional activators, including herpes simplex virus type 1 VP16 (89). These results suggest that proteolysis of E1A, and that of potentially other locally associated chromatin bound factors, is required to promote subsequent rounds of transcriptional initiation and contributes to the potency of transcriptional activation by CR3.

AR1, which in HAdV-5 E1A is a series of six repeats of EP, is consistently predicted to be structurally disordered (Fig. (Fig.2).2). The target(s) of AR1 remains to be identified, but it is known that the overall negative charge is critical to its function, whereas glycine can substitute for the prolines without a loss of function (124).

The assembly of an active transcription initiation complex by CR3 begins with the recruitment of E1A to the template via interaction with sequence-specific DNA binding transcription factors. CR3 subsequently orchestrates the nucleation of multiple key transcriptional regulators via distinct subdomains. CR3 appears to be an example where an ordered region, required for specific interaction with few targets (TBP and MED23), is juxtaposed to a disordered region required for promiscuous interaction with multiple promoter-targeting transcription factors. The result is a compact, yet potent, activation domain capable of activating multiple promoter regions.


Despite more than two decades of extensive study, relatively little is known about the function and binding partners that associate with E1A via its C terminus. In HAdV-5 E1A, CR4 spans residues 240 to 288 (4). This region is required for oncogenic transformation of rodent cells in cooperation with E1B (24, 126) but, paradoxically, it suppresses transformation in cooperation with activated ras (11, 125). This region of E1A is also necessary to activate transcription of epithelium-specific genes, inducing a mesenchymal-to-epithelial transition (47, 114). Software predictions suggest that most of the region encoded by the second exon is largely unstructured, with subregions showing a propensity to form structure. As noted above for other regions, the extreme C terminus of HAdV-12 E1A is predicted to be largely structured, whereas the E1A proteins of other serotypes are not (Fig. (Fig.22).

There are only a few known proteins that associate with this region of E1A, and their interactions generally map within CR4. These include the CtBP family (11, 114) and dual-specificity tyrosine (Y) phosphorylation-regulated kinase (Dyrk1A) and Dyrk1B (148). The extreme C terminus of the major E1A proteins also contains a canonical nuclear localization signal, consisting of the sequence KRPRP (residues 285 to 289 in HAdV-5 E1A), which directly interacts with importin-α and directs rapid nuclear import of E1A (67, 79).

The best-characterized interaction of the C terminus/CR4 is with CtBP, which was originally identified based on its association with E1A. An N-terminal region of CtBP binds to a PXDLS motif (residues 279 to 283 in HAdV-5 E1A) (114) that is present in all the currently sequenced HAdV E1A proteins (4) and a number of cellular transcription factors (Fig. (Fig.1).1). CtBP is a transcriptional corepressor that dimerizes upon NADH binding. When recruited to a cellular promoter by a sequence-specific transcription factor, it directs the formation of a silencing complex. CtBP primarily represses proapoptotic and epithelial gene expression (17). E1A inhibits CtBP targeting by competing with cellular PXDLS-containing factors. This leads to a derepression of transcription. Alternatively, E1A could potentially use the CtBP dimer to access specific repressed promoters and subsequently recruit coactivators to turn on gene transcription, but this has not been tested.

In agreement with the prediction that the CtBP binding region of HAdV-12 is inherently structured, a short, 14-residue peptide encompassing the PXDLS region of HAdV-12 E1A binds to CtBP with an affinity approximately 10-fold higher than that of a corresponding peptide from HAdV-5 E1A (91). The reason HAdV-12 E1A differs from the other serotypes is not known, and the functional consequences of this difference remain to be explored. Nuclear magnetic resonance analysis indicates that the PXDLS portion of the HAdV-12 peptide forms a series of β-turns when free in solution (91). However, upon binding to CtBP, this portion of the peptide changes to form an extended α-helix and can thus be considered an α-MoRF (90). The residues N-terminal of the PXDLS motif are predicted to be predominantly structured (Fig. (Fig.2)2) and have been shown to form an α-helix in solution (90). The proline residue in the PXDLS motif of HAdV-12 is probably important in disrupting this α-helix prior to interaction with CtBP. Upon binding to CtBP, the proline residue has been suggested to act as a “helix inducer” by driving the β-to-α conformational switch of the PXDLS motif in the presence of CtBP1 (90). Similar structural features are observed for most other PXDLS-containing cellular and viral proteins, and they are likely important in CtBP binding. The exact contacts made between the HAdV-12 C terminus and CtBP remain to be elucidated, but they are likely driven by hydrophobic interactions with an N-terminal hydrophobic cleft in CtBP as reported for other PXDLS-containing proteins (96, 149). Intriguingly, the C terminus of CtBP has recently been reported to lack structure (97). This region may be important in the function of the protein as a promiscuous transcriptional corepressor that targets numerous factors, and lack of structure could facilitate binding to a large variety of binding partners.

Dyrk1A and -1B are highly related dual-specificity kinases that have been implicated in regulating cell survival, proliferation, and differentiation (86). It is unclear why E1A targets Dyrk1A and -1B, but the interaction with E1A stimulates their kinase activity in vitro and their binding overlaps the CtBP binding site (148). In an interesting parallel, the immortalization of keratinocytes by HPV16 E7 results in an increase in Dryk1A expression, and a similar increase in Dyrk1A expression is present in malignant HPV-positive cervical cancers, where it has been proposed to function as an antiapototic factor (15). E1A may utilize Dyrk1A as a survival factor in a manner similar to that of HPV E7, but this remains to be determined.


The proteins encoded by adenovirus E1A are multifunctional regulators of transcription and the cell cycle. The E1A proteins serve as viral molecular hubs that physically interact with and coordinate the actions of dozens of diverse cellular proteins, many of which are molecular hubs themselves. There is no atomic structure available for E1A and it has no known cellular orthologs. Mutational analysis and structural predictions suggest that E1A exists largely in a natively unfolded conformation. Intrinsic structural disorder in E1A likely confers promiscuity in target binding and most likely forms the basis for the multifunctional properties of E1A, which is necessary for virus growth. Currently, there are many identified or predicted MoRFs and LMs within E1A, which makes it a rich discovery platform for these short, interaction-prone segments of protein disorder as well as a useful tool for dissecting cell regulation. Indeed, the interaction of E1A with individual mammalian regulatory proteins, and the resulting effects on their normal function, has been heavily exploited to elucidate the molecular basis by which they control cellular processes (7, 34, 36, 38, 94, 116). Furthermore, our understanding of the structure/function relationship in E1A is already being utilized in the development of conditionally replicating HAdV-5 as an oncolytic agent (45, 52, 54, 105), and E1A itself is undergoing clinical trials as an antitumor therapy based on its anti-oncogenic effects (53, 80, 134, 145). One area that remains largely undetermined is an integrated systems biology type of analysis of how the viral E1A hub cross-couples existing cellular network components by establishing new connections. Clearly, the concurrent association of E1A with multiple cellular proteins, many of which with intrinsic enzymatic activity, has the potential to establish novel infection-specific pathways (14, 137, 150). Thus, the isolation and study of new targets of E1A continue to provide an exciting opportunity to identify and dissect critical mechanisms controlling mammalian transcription, immunity, and growth and differentiation, as well as translational applications.


This work was supported by grants from the Canadian Institutes of Health Research and Natural Sciences and Engineering Research Council of Canada. A.F.Y. was supported by an Ontario Graduate Scholarship, and J.N.G.A. was supported by an Ontario Graduate Scholarship in Science and Technology.

We thank F. Dick and R. Grand for helpful discussions.


[down-pointing small open triangle]Published ahead of print on 2 April 2008.


1. Alevizopoulos, K., B. Sanchez, and B. Amati. 2000. Conserved region 2 of adenovirus E1A has a function distinct from pRb binding required to prevent cell cycle arrest by p16INK4a or p27Kip1. Oncogene 192067-2074. [PubMed]
2. Ansieau, S., and A. Leutz. 2002. The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif. J. Biol. Chem. 2774906-4910. [PubMed]
3. Arany, Z., D. Newsome, E. Oldread, D. M. Livingston, and R. Eckner. 1995. A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. Nature 37481-84. [PubMed]
4. Avvakumov, N., A. E. Kajon, R. C. Hoeben, and J. S. Mymryk. 2004. Comprehensive sequence analysis of the E1A proteins of human and simian adenoviruses. Virology 329477-492. [PubMed]
5. Avvakumov, N., R. Wheeler, J. C. D'Halluin, and J. S. Mymryk. 2002. Comparative sequence analysis of the largest E1A proteins of human and simian adenoviruses. J. Virol. 767968-7975. [PMC free article] [PubMed]
6. Barbeau, D., R. Charbonneau, S. G. Whalen, S. T. Bayley, and P. E. Branton. 1994. Functional interactions within adenovirus E1A protein complexes. Oncogene 9359-373. [PubMed]
7. Bayley, S. T., and J. S. Mymryk. 1994. Adenovirus E1A proteins and transformation. Int. J. Oncology 5425-444. [PubMed]
8. Berk, A. J. 2005. Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. Oncogene 247673-7685. [PubMed]
9. Bondesson, M., M. Mannervik, G. Akusjarvi, and C. Svensson. 1994. An adenovirus E1A transcriptional repressor domain functions as an activator when tethered to a promoter. Nucleic Acids Res. 223053-3060. [PMC free article] [PubMed]
10. Boyd, J. M., P. M. Loewenstein, Q. Q. Tang Qq, L. Yu, and M. Green. 2002. Adenovirus E1A N-terminal amino acid sequence requirements for repression of transcription in vitro and in vivo correlate with those required for E1A interference with TBP-TATA complex formation. J. Virol. 761461-1474. [PMC free article] [PubMed]
11. Boyd, J. M., T. Subramanian, U. Schaeper, M. La Regina, S. Bayley, and G. Chinnadurai. 1993. A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J. 12469-478. [PMC free article] [PubMed]
12. Boyer, T. G., M. E. Martin, E. Lees, R. P. Ricciardi, and A. J. Berk. 1999. Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Nature 399276-279. [PubMed]
13. Carr, D. W., R. E. Stofko-Hahn, I. D. Fraser, S. M. Bishop, T. S. Acott, R. G. Brennan, and J. D. Scott. 1991. Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif. J. Biol. Chem. 26614188-14192. [PubMed]
14. Chan, H. M., M. Krstic-Demonacos, L. Smith, C. Demonacos, and N. B. La Thangue. 2001. Acetylation control of the retinoblastoma tumour-suppressor protein. Nat. Cell Biol. 3667-674. [PubMed]
15. Chang, H. S., C. H. Lin, C. H. Yang, M. S. Yen, C. R. Lai, Y. R. Chen, Y. J. Liang, and W. C. Yu. 2007. Increased expression of Dyrk1a in HPV16 immortalized keratinocytes enable evasion of apoptosis. Int. J. Cancer 1202377-2385. [PubMed]
16. Chinnadurai, G. 2002. CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol. Cell 9213-224. [PubMed]
17. Chinnadurai, G. 2007. Transcriptional regulation by C-terminal binding proteins. Int. J. Biochem. Cell Biol. 391593-1607. [PubMed]
18. Culp, J. S., L. C. Webster, D. J. Friedman, C. L. Smith, W.-J. Huang, F. Y.-H. Wu, M. Rosenberg, and R. P. Ricciardi. 1988. The 289-amino acid E1A protein of adenovirus binds zinc in a region that is important for trans-activation. Proc. Natl. Acad. Sci. USA 856450-6454. [PMC free article] [PubMed]
19. Deleu, L., S. Shellard, K. Alevizopoulos, B. Amati, and H. Land. 2001. Recruitment of TRRAP required for oncogenic transformation by E1A. Oncogene 208270-8275. [PubMed]
20. De Luca, A., R. Mangiacasale, A. Severino, L. Malquori, A. Baldi, A. Palena, A. M. Mileo, P. Lavia, and M. G. Paggi. 2003. E1A deregulates the centrosome cycle in a Ran GTPase-dependent manner. Cancer Res. 631430-1437. [PubMed]
21. Deng, J., F. Kloosterbooer, W. Xia, and M. C. Hung. 2002. The NH2-terminal and conserved region 2 domains of adenovirus E1A mediate two distinct mechanisms of tumor suppression. Cancer Res. 62346-350. [PubMed]
22. DeRan, M., M. Pulvino, E. Greene, C. Su, and J. Zhao. 2008. Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition. Mol. Cell. Biol. 28435-447. [PMC free article] [PubMed]
23. Dick, F. A., and N. J. Dyson. 2002. Three regions of the pRB pocket domain affect its inactivation by human papillomavirus E7 proteins. J. Virol. 766224-6234. [PMC free article] [PubMed]
24. Douglas, J. L., and M. P. Quinlan. 1995. Efficient nuclear localization and immortalizing ability, two functions dependent on the adenovirus type 5 (Ad5) E1A second exon, are necessary for cotransformation with Ad5 E1B but not with T24ras. J. Virol. 698061-8065. [PMC free article] [PubMed]
25. Dunker, A. K., M. S. Cortese, P. Romero, L. M. Iakoucheva, and V. N. Uversky. 2005. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 2725129-5148. [PubMed]
26. Dyson, H. J., and P. E. Wright. 2005. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell Biol. 6197-208. [PubMed]
27. Eckner, R., M. E. Ewen, D. Newsome, M. Gerdes, J. A. DeCaprio, J. B. Lawrence, and D. M. Livingston. 1994. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 8869-884. [PubMed]
28. Egan, C., T. N. Jelsma, J. A. Howe, S. T. Bayley, B. Ferguson, and P. E. Branton. 1988. Mapping of cellular protein-binding sites on the products of early-region 1A of human adenovirus type 5. Mol. Cell. Biol. 83955-3959. [PMC free article] [PubMed]
29. Fahnestock, M. L., and J. B. Lewis. 1989. Genetic dissection of the transactivating domain of the E1a 289R protein of adenovirus type 2. J. Virol. 631495-1504. [PMC free article] [PubMed]
30. Fattaey, A. R., E. Harlow, and K. Helin. 1993. Independent regions of adenovirus E1A are required for binding to and dissociation of E2F-protein complexes. Mol. Cell. Biol. 137267-7277. [PMC free article] [PubMed]
31. Fax, P., C. R. Carlson, P. Collas, K. Taskén, H. Esche, and D. Brockmann. 2001. Binding of PKA-RIIα to the adenovirus E1A12S oncoprotein correlates with its nuclear translocation and an increase in PKA-dependent promoter activity. Virology 28530-41. [PubMed]
32. Felsani, A., A. M. Mileo, and M. G. Paggi. 2006. Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene 255277-5285. [PubMed]
33. Figge, J., T. Webster, T. F. Smith, and E. Paucha. 1988. Prediction of similar transforming regions in simian virus 40 large T, adenovirus E1A, and myc oncoproteins. J. Virol. 621814-1818. [PMC free article] [PubMed]
34. Flint, J., and T. Shenk. 1997. Viral transactivating proteins. Annu. Rev. Genet. 31177-212. [PubMed]
35. Fraser, H. B., A. E. Hirsh, L. M. Steinmetz, C. Scharfe, and M. W. Feldman. 2002. Evolutionary rate in the protein interaction network. Science 296750-752. [PubMed]
36. Frisch, S. M., and J. S. Mymryk. 2002. Adenovirus-5 E1A: paradox and paradigm. Nat. Rev. Mol. Cell Biol. 3441-452. [PubMed]
37. Fuchs, M., J. Gerber, R. Drapkin, S. Sif, T. Ikura, V. Ogryzko, W. S. Lane, Y. Nakatani, and D. M. Livingston. 2001. The p400 complex is an essential E1A transformation target. Cell 106297-307. [PubMed]
38. Gallimore, P. H., and A. S. Turnell. 2001. Adenovirus E1A: remodelling the host cell, a life or death experience. Oncogene 207824-7835. [PubMed]
39. Gandhi, T. K., J. Zhong, S. Mathivanan, L. Karthick, K. N. Chandrika, S. S. Mohan, S. Sharma, S. Pinkert, S. Nagaraju, B. Periaswamy, G. Mishra, K. Nandakumar, B. Shen, N. Deshpande, R. Nayak, M. Sarker, J. D. Boeke, G. Parmigiani, J. Schultz, J. S. Bader, and A. Pandey. 2006. Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat. Genet. 38285-293. [PubMed]
40. Gedrich, R. W., S. T. Bayley, and D. A. Engel. 1992. Induction of AP-1 DNA-binding activity and c-fos mRNA by the adenovirus 243R E1A protein and cyclic AMP requires domains necessary for transformation. J. Virol. 665849-5859. [PMC free article] [PubMed]
41. Geisberg, J. V., J. L. Chen, and R. P. Ricciardi. 1995. Subregions of the adenovirus E1A transactivation domain target multiple components of the TFIID complex. Mol. Cell. Biol. 156283-6290. [PMC free article] [PubMed]
42. Geisberg, J. V., W. S. Lee, A. J. Berk, and R. P. Ricciardi. 1994. The zinc finger region of the adenovirus E1A transactivating domain complexes with the TATA box binding protein. Proc. Natl. Acad. Sci. USA 912488-2492. [PMC free article] [PubMed]
43. Girdwood, D., D. Bumpass, O. A. Vaughan, A. Thain, L. A. Anderson, A. W. Snowden, E. Garcia-Wilson, N. D. Perkins, and R. T. Hay. 2003. P300 transcriptional repression is mediated by SUMO modification. Mol. Cell 111043-1054. [PubMed]
44. Gold, M. G., B. Lygren, P. Dokurno, N. Hoshi, G. McConnachie, K. Tasken, C. R. Carlson, J. D. Scott, and D. Barford. 2006. Molecular basis of AKAP specificity for PKA regulatory subunits. Mol. Cell 24383-395. [PubMed]
45. Gomez-Manzano, C., C. Balague, R. Alemany, M. G. Lemoine, P. Mitlianga, H. Jiang, A. Khan, M. Alonso, F. F. Lang, C. A. Conrad, T. J. Liu, B. N. Bekele, W. K. Yung, and J. Fueyo. 2004. A novel E1A-E1B mutant adenovirus induces glioma regression in vivo. Oncogene 231821-1828. [PubMed]
46. Grand, R. J., A. S. Turnell, G. G. Mason, W. Wang, A. E. Milner, J. S. Mymryk, S. M. Rookes, A. J. Rivett, and P. H. Gallimore. 1999. Adenovirus early region 1A protein binds to mammalian SUG1-a regulatory component of the proteasome. Oncogene 18449-458. [PubMed]
47. Grooteclaes, M. L., and S. M. Frisch. 2000. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 193823-3828. [PubMed]
48. Han, J. D., N. Bertin, T. Hao, D. S. Goldberg, G. F. Berriz, L. V. Zhang, D. Dupuy, A. J. Walhout, M. E. Cusick, F. P. Roth, and M. Vidal. 2004. Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 43088-93. [PubMed]
49. Hateboer, G., A. Gennissen, Y. F. Ramos, R. M. Kerkhoven, V. Sonntag Buck, H. G. Stunnenberg, and R. Bernards. 1995. BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation. EMBO J. 143159-3169. [PMC free article] [PubMed]
50. Hateboer, G., E. M. Hijmans, J. B. Nooij, S. Schlenker, S. Jentsch, and R. Bernards. 1996. mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect. J. Biol. Chem. 27125906-25911. [PubMed]
51. Heck, D. V., C. L. Yee, P. M. Howley, and K. Munger. 1992. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc. Natl. Acad. Sci. USA 894442-4446. [PMC free article] [PubMed]
52. Heise, C., T. Hermiston, L. Johnson, G. Brooks, A. Sampson-Johannes, A. Williams, L. Hawkins, and D. Kirn. 2000. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat. Med. 61134-1139. [PubMed]
53. Hortobagyi, G. N., N. T. Ueno, W. Xia, S. Zhang, J. K. Wolf, J. B. Putnam, P. L. Weiden, J. S. Willey, M. Carey, D. L. Branham, J. Y. Payne, S. D. Tucker, C. Bartholomeusz, R. G. Kilbourn, R. L. De Jager, N. Sneige, R. L. Katz, P. Anklesaria, N. K. Ibrahim, J. L. Murray, R. L. Theriault, V. Valero, D. M. Gershenson, M. W. Bevers, L. Huang, G. Lopez-Berestein, and M. C. Hung. 2001. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J. Clin. Oncol. 193422-3433. [PubMed]
54. Howe, J. A., G. W. Demers, D. E. Johnson, S. E. Neugebauer, S. T. Perry, M. T. Vaillancourt, and B. Faha. 2000. Evaluation of E1-mutant adenoviruses as conditionally replicating agents for cancer therapy. Mol. Ther. 2485-495. [PubMed]
55. Hu, X., and M. A. Lazar. 1999. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 40293-96. [PubMed]
56. Hughes-Davies, L., D. Huntsman, M. Ruas, F. Fuks, J. Bye, S. F. Chin, J. Milner, L. A. Brown, F. Hsu, B. Gilks, T. Nielsen, M. Schulzer, S. Chia, J. Ragaz, A. Cahn, L. Linger, H. Ozdag, E. Cattaneo, E. S. Jordanova, E. Schuuring, D. S. Yu, A. Venkitaraman, B. Ponder, A. Doherty, S. Aparicio, D. Bentley, C. Theillet, C. P. Ponting, C. Caldas, and T. Kouzarides. 2003. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115523-535. [PubMed]
57. Iakoucheva, L. M., C. J. Brown, J. D. Lawson, Z. Obradovic, and A. K. Dunker. 2002. Intrinsic disorder in cell-signaling and cancer-associated proteins. J. Mol. Biol. 323573-584. [PubMed]
58. Ikeda, M.-A., and J. R. Nevins. 1993. Identification of distinct roles for separate E1A domains in disruption of E2F complexes. Mol. Cell. Biol. 137029-7035. [PMC free article] [PubMed]
59. Isobe, T., C. Uchida, T. Hattori, K. Kitagawa, T. Oda, and M. Kitagawa. 2006. Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. Biochem. Biophys. Res. Commun. 339367-374. [PubMed]
60. Jelsma, T. N., J. A. Howe, C. M. Evelegh, N. F. Cunniff, M. H. Skiadopoulos, M. R. Floroff, J. E. Denman, and S. T. Bayley. 1988. Use of deletion and point mutants spanning the coding region of the adenovirus 5 E1A gene to define a domain that is essential for transcriptional activation. Virology 163494-502. [PubMed]
61. Jelsma, T. N., J. A. Howe, J. S. Mymryk, C. M. Evelegh, N. F. A. Cunniff, and S. T. Bayley. 1989. Sequences in E1A proteins of human adenovirus 5 required for cell transformation, repression of a transcriptional enhancer, and induction of proliferating cell nuclear antigen. Virology 171120-130. [PubMed]
62. Jeong, H., S. P. Mason, A. L. Barabasi, and Z. N. Oltvai. 2001. Lethality and centrality in protein networks. Nature 41141-42. [PubMed]
63. Johnson, E. S. 2004. Protein modification by SUMO. Annu. Rev. Biochem. 73355-382. [PubMed]
64. Jones, N., and T. Shenk. 1979. An adenovirus type 5 early gene function regulates expression of other early viral genes. Proc. Natl. Acad. Sci. USA 763665-3669. [PMC free article] [PubMed]
65. Kagey, M. H., T. A. Melhuish, and D. Wotton. 2003. The polycomb protein Pc2 is a SUMO E3. Cell 113127-137. [PubMed]
66. Kimelman, D., J. S. Miller, D. Porter, and B. E. Roberts. 1985. E1a regions of the human adenoviruses and of the highly oncogenic simian adenovirus 7 are closely related. J. Virol. 53399-409. [PMC free article] [PubMed]
67. Köhler, M., D. Görlich, E. Hartmann, and J. Franke. 2001. Adenoviral E1A protein nuclear import is preferentially mediated by importin α3 in vitro. Virology 289186-191. [PubMed]
68. Krippl, B., B. Ferguson, M. Rosenberg, and H. Westphal. 1984. Functions of purified E1A protein microinjected into mammalian cells. Proc. Natl. Acad. Sci. USA 816988-6992. [PMC free article] [PubMed]
69. Kuppuswamy, M. N., and G. Chinnadurai. 1987. Relationship between the transforming and transcriptional regulatory functions of adenovirus 2 E1a oncogene. Virology 15931-38. [PubMed]
70. Ladendorff, N. E., S. Wu, and J. S. Lipsick. 2001. BS69, an adenovirus E1A-associated protein, inhibits the transcriptional activity of c-Myb. Oncogene 20125-132. [PubMed]
71. Ledl, A., D. Schmidt, and S. Muller. 2005. Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor. Oncogene 243810-3818. [PubMed]
72. Lee, J. O., A. A. Russo, and N. P. Pavletich. 1998. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 391859-865. [PubMed]
73. Lillie, J. W., M. Green, and M. R. Green. 1986. An adenovirus E1a protein region required for transformation and transcriptional repression. Cell 461043-1051. [PubMed]
74. Lillie, J. W., and M. R. Green. 1989. Transcription activation by the adenovirus E1a protein. Nature 33839-44. [PubMed]
75. Lipinski, K. S., H. Esche, and D. Brockmann. 1998. Amino acids 1-29 of the adenovirus serotypes 12 and 2 E1A proteins interact with rap30 (TFIIF) and TBP in vitro. Virus Res. 5499-106. [PubMed]
76. Liu, F., and M. R. Green. 1990. A specific member of the ATF transcription factor family can mediate transcription activation by the adenovirus E1a protein. Cell 611217-1224. [PubMed]
77. Liu, F., and M. R. Green. 1994. Promoter targeting by adenovirus E1a through interaction with different cellular DNA-binding domains. Nature 368520-525. [PubMed]
78. Liu, X., and R. Marmorstein. 2007. Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor. Genes Dev. 212711-2716. [PMC free article] [PubMed]
79. Lyons, R. H., B. Q. Ferguson, and M. Rosenberg. 1987. Pentapeptide nuclear localization signal in adenovirus E1a. Mol. Cell. Biol. 72451-2456. [PMC free article] [PubMed]
80. Madhusudan, S., A. Tamir, N. Bates, E. Flanagan, M. E. Gore, D. P. Barton, P. Harper, M. Seckl, H. Thomas, N. R. Lemoine, M. Charnock, N. A. Habib, R. Lechler, J. Nicholls, M. Pignatelli, and T. S. Ganesan. 2004. A multicenter phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene. Clin. Cancer Res. 102986-2996. [PubMed]
81. Martin, K. J., J. W. Lillie, and M. R. Green. 1990. Evidence for interaction of different eukaryotic transcriptional activators with distinct cellular targets. Nature 346147-152. [PubMed]
82. Maslov, S., and K. Sneppen. 2002. Specificity and stability in topology of protein networks. Science 296910-913. [PubMed]
83. Mazzarelli, J. M., G. B. Atkins, J. V. Geisberg, and R. P. Ricciardi. 1995. The viral oncoproteins Ad5 E1A, HPV16 E7 and SV40 TAg bind a common region of the TBP-associated factor-110. Oncogene 111859-1864. [PubMed]
84. Meng, X., P. Webb, Y. F. Yang, M. Shuen, A. F. Yousef, J. D. Baxter, J. S. Mymryk, and P. G. Walfish. 2005. E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode. Proc. Natl. Acad. Sci. USA 1026267-6272. [PMC free article] [PubMed]
85. Meng, X., Y. F. Yang, X. Cao, M. V. Govindan, M. Shuen, A. N. Hollenberg, J. S. Mymryk, and P. G. Walfish. 2003. Cellular context of coregulator and adaptor proteins regulates human adenovirus 5 early region 1A-dependent gene activation by the thyroid hormone receptor. Mol. Endocrinol. 171095-1105. [PubMed]
86. Mercer, S. E., and E. Friedman. 2006. Mirk/Dyrk1B: a multifunctional dual-specificity kinase involved in growth arrest, differentiation, and cell survival. Cell Biochem. Biophys. 45303-315. [PubMed]
87. Mittnacht, S., J. A. Lees, D. Desai, E. Harlow, D. O. Morgan, and R. A. Weinberg. 1994. Distinct sub-populations of the retinoblastoma protein show a distinct pattern of phosphorylation. EMBO J. 13118-127. [PMC free article] [PubMed]
88. Mohan, A., C. J. Oldfield, P. Radivojac, V. Vacic, M. S. Cortese, A. K. Dunker, and V. N. Uversky. 2006. Analysis of molecular recognition features (MoRFs). J. Mol. Biol. 3621043-1059. [PubMed]
89. Molinari, E., M. Gilman, and S. Natesan. 1999. Proteasome-mediated degradation of transcriptional activators correlates with activation domain potency in vivo. EMBO J. 186439-6447. [PMC free article] [PubMed]
90. Molloy, D. P., P. M. Barral, P. H. Gallimore, and R. J. Grand. 2007. The effect of CtBP1 binding on the structure of the C-terminal region of adenovirus 12 early region 1A. Virology 363342-356. [PubMed]
91. Molloy, D. P., A. E. Milner, I. K. Yakub, G. Chinnadurai, P. H. Gallimore, and R. J. Grand. 1998. Structural determinants present in the C-terminal binding protein binding site of adenovirus early region 1A proteins. J. Biol. Chem. 27320867-20876. [PubMed]
92. Moran, E., B. Zerler, T. M. Harrison, and M. B. Mathew. 1986. Identification of separate domains in the adenovirus E1A gene for immortalization activity and the activation of virus early genes. Mol. Cell. Biol. 63470-3480. [PMC free article] [PubMed]
93. Morris, E. J., and N. J. Dyson. 2001. Retinoblastoma protein partners. Adv. Cancer Res. 821-54. [PubMed]
94. Mymryk, J. S. 1996. Tumour suppressive properties of the adenovirus 5 E1A oncogene. Oncogene 131581-1589. [PubMed]
95. Mymryk, J. S., K. Shire, and S. T. Bayley. 1994. Induction of apoptosis by adenovirus type 5 E1A in rat cells requires a proliferation block. Oncogene 91187-1193. [PubMed]
96. Nardini, M., S. Spano, C. Cericola, A. Pesce, A. Massaro, E. Millo, A. Luini, D. Corda, and M. Bolognesi. 2003. CtBP/BARS: a dual-function protein involved in transcription co-repression and Golgi membrane fission. EMBO J. 223122-3130. [PMC free article] [PubMed]
97. Nardini, M., D. Svergun, P. V. Konarev, S. Spano, M. Fasano, C. Bracco, A. Pesce, A. Donadini, C. Cericola, F. Secundo, A. Luini, D. Corda, and M. Bolognesi. 2006. The C-terminal domain of the transcriptional corepressor CtBP is intrinsically unstructured. Protein Sci. 151042-1050. [PMC free article] [PubMed]
98. Nevins, J. R., H. S. Ginsberg, J. M. Blanchard, M. C. Wilson, and J. E. Darnell. 1979. Regulation of the primary expression of the early adenovirus transcription units. J. Virol. 32727-733. [PMC free article] [PubMed]
99. Nevins, J. R., and P. K. Vogt. 1996. Cell transformation by viruses, p. 267-309. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fundamental virology. Lippincott-Raven, Philadelphia, PA.
100. O'Connor, M. J., H. Zimmermann, S. Nielsen, H. U. Bernard, and T. Kouzarides. 1999. Characterization of an E1A-CBP interaction defines a novel transcriptional adapter motif (TRAM) in CBP/p300. J. Virol. 733574-3581. [PMC free article] [PubMed]
101. Ohlenschläger, O., T. Seiboth, H. Zengerling, L. Briese, A. Marchanka, R. Ramachandran, M. Baum, M. Korbas, W. Meyer-Klaucke, M. Dürst, and M. Görlach. 2006. Solution structure of the partially folded high-risk human papilloma virus 45 oncoprotein E7. Oncogene 255953-5959. [PubMed]
102. Pelka, P., A. Scime, C. Mandalfino, M. Joch, P. Abdulla, and P. Whyte. 2007. Adenovirus E1A proteins direct subcellular redistribution of Nek9, a NimA-related kinase. J. Cell Physiol. 21213-25. [PubMed]
103. Perissi, V., L. M. Staszewski, E. M. McInerney, R. Kurokawa, A. Krones, D. W. Rose, M. H. Lambert, M. V. Milburn, C. K. Glass, and M. G. Rosenfeld. 1999. Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 133198-3208. [PMC free article] [PubMed]
104. Phelps, W. C., C. L. Yee, K. Munger, and P. M. Howley. 1988. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell 53539-547. [PubMed]
105. Ramachandra, M., A. Rahman, A. Zou, M. Vaillancourt, J. A. Howe, D. Antelman, B. Sugarman, G. W. Demers, H. Engler, D. Johnson, and P. Shabram. 2001. Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nat. Biotechnol. 191035-1041. [PubMed]
106. Rasti, M., R. J. Grand, J. S. Mymryk, P. H. Gallimore, and A. S. Turnell. 2005. Recruitment of CBP/p300, TATA-binding protein, and S8 to distinct regions at the N terminus of adenovirus E1A. J. Virol. 795594-5605. [PMC free article] [PubMed]
107. Rasti, M., R. J. Grand, A. F. Yousef, M. Shuen, J. S. Mymryk, P. H. Gallimore, and A. S. Turnell. 2006. Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription. EMBO J. 252710-2722. [PMC free article] [PubMed]
108. Reid, J. L., A. J. Bannister, P. Zegerman, M. A. Martinez-Balbas, and T. Kouzarides. 1998. E1A directly binds and regulates the P/CAF acetyltransferase. EMBO J. 174469-4477. [PMC free article] [PubMed]
109. Romero, P., Z. Obradovic, and A. K. Dunker. 2004. Natively disordered proteins: functions and predictions. Appl. Bioinformatics 3105-113. [PubMed]
110. Rowe, D. T., F. L. Graham, and P. E. Branton. 1983. Intracellular localization of adenovirus type 5 tumor antigens in productively infected cells. Virology 129456-468. [PubMed]
111. Rual, J. F., K. Venkatesan, T. Hao, T. Hirozane-Kishikawa, A. Dricot, N. Li, G. F. Berriz, F. D. Gibbons, M. Dreze, N. Ayivi-Guedehoussou, N. Klitgord, C. Simon, M. Boxem, S. Milstein, J. Rosenberg, D. S. Goldberg, L. V. Zhang, S. L. Wong, G. Franklin, S. Li, J. S. Albala, J. Lim, C. Fraughton, E. Llamosas, S. Cevik, C. Bex, P. Lamesch, R. S. Sikorski, J. Vandenhaute, H. Y. Zoghbi, A. Smolyar, S. Bosak, R. Sequerra, L. Doucette-Stamm, M. E. Cusick, D. E. Hill, F. P. Roth, and M. Vidal. 2005. Towards a proteome-scale map of the human protein-protein interaction network. Nature 4371173-1178. [PubMed]
112. Sang, N., A. Severino, P. Russo, A. Baldi, A. Giordano, A. M. Mileo, M. G. Paggi, and A. De Luca. 2001. RACK1 interacts with E1A and rescues E1A-induced yeast growth inhibition and mammalian cell apoptosis. J. Biol. Chem. 27627026-27033. [PubMed]
113. Schaack, J., M. L. Bennett, J. D. Colbert, A. V. Torres, G. H. Clayton, D. Ornelles, and J. Moorhead. 2004. E1A and E1B proteins inhibit inflammation induced by adenovirus. Proc. Natl. Acad. Sci. USA 1013124-3129. [PMC free article] [PubMed]
114. Schaeper, U., J. M. Boyd, S. Verma, E. Uhlmann, T. Subramanian, and G. Chinnadurai. 1995. Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc. Natl. Acad. Sci. USA 9210467-10471. [PMC free article] [PubMed]
115. Schneider, J. F., F. Fisher, C. R. Goding, and N. C. Jones. 1987. Mutational analysis of the adenovirus E1a gene: the role of transcriptional regulation in transformation. EMBO J. 62053-2060. [PMC free article] [PubMed]
116. Shenk, T., and J. Flint. 1991. Transcriptional and transforming activities of the adenovirus E1A proteins. Adv. Cancer Res. 5747-85. [PubMed]
117. Shisler, J., P. Duerksen-Hughes, T. M. Hermiston, W. S. M. Wold, and L. R. Gooding. 1996. Induction of susceptibility to tumor necrosis factor by E1A is dependent on binding to either p300 or p105-Rb and induction of DNA synthesis. J. Virol. 7068-77. [PMC free article] [PubMed]
118. Somasundaram, K., G. Jayaraman, T. Williams, E. Moran, S. Frisch, and B. Thimmapaya. 1996. Repression of a matrix metalloprotease gene by E1A correlates with its ability to bind to cell type-specific transcription factor AP-2. Proc. Natl. Acad. Sci. USA 933088-3093. [PMC free article] [PubMed]
119. Song, C. Z., P. M. Loewenstein, K. Toth, and M. Green. 1995. Transcription factor TFIID is a direct functional target of the adenovirus E1A transcription-repression domain. Proc. Natl. Acad. Sci. USA 9210330-10333. [PMC free article] [PubMed]
120. Spector, D. J., M. McGrogan, and H. J. Raskas. 1978. Regulation of the appearance of cytoplasmic RNAs from region 1 of the adenovirus 2 genome. J. Mol. Biol. 126395-414. [PubMed]
121. Stein, R. W., M. Corrigan, P. Yaciuk, J. Whelan, and E. Moran. 1990. Analysis of E1A-mediated growth regulation functions: binding of the 300-kilodalton cellular product correlates with E1A enhancer repression function and DNA synthesis-inducing activity. J. Virol. 644421-4427. [PMC free article] [PubMed]
122. Stelzl, U., U. Worm, M. Lalowski, C. Haenig, F. H. Brembeck, H. Goehler, M. Stroedicke, M. Zenkner, A. Schoenherr, S. Koeppen, J. Timm, S. Mintzlaff, C. Abraham, N. Bock, S. Kietzmann, A. Goedde, E. Toksoz, A. Droege, S. Krobitsch, B. Korn, W. Birchmeier, H. Lehrach, and E. E. Wanker. 2005. A human protein-protein interaction network: a resource for annotating the proteome. Cell 122957-968. [PubMed]
123. Stephens, C., and E. Harlow. 1987. Differential splicing yields novel adenovirus 5 E1A mRNAs that encode 30 kd and 35 kd proteins. EMBO J. 62027-2035. [PMC free article] [PubMed]
124. Ström, A. C., P. Ohlsson, and G. Akusjarvi. 1998. AR1 is an integral part of the adenovirus type 2 E1A-CR3 transactivation domain. J. Virol. 725978-5983. [PMC free article] [PubMed]
125. Subramanian, T., M. La Regina, and G. Chinnadurai. 1989. Enhanced ras oncogene mediated cell transformation and tumorigenesis by adenovirus 2 mutants lacking the C-terminal region of E1a protein. Oncogene 4415-420. [PubMed]
126. Subramanian, T., S. E. Malstrom, and G. Chinnadurai. 1991. Requirement of the C-terminal region of adenovirus E1a for cell transformation in cooperation with E1b. Oncogene 61171-1173. [PubMed]
127. Taylor, D. A., V. B. Kraus, J. J. Schwarz, E. N. Olson, and W. E. Kraus. 1993. E1A-mediated inhibition of myogenesis correlates with a direct physical interaction of E1A12S and basic helix-loop-helix proteins. Mol. Cell. Biol. 134714-4727. [PMC free article] [PubMed]
128. Turnell, A. S., R. J. Grand, C. Gorbea, X. Zhang, W. Wang, J. S. Mymryk, and P. H. Gallimore. 2000. Regulation of the 26S proteasome by adenovirus E1A. EMBO J. 194759-4773. [PMC free article] [PubMed]
129. Ulfendahl, P. J., S. Linder, J.-P. Kreivi, K. Nordqvist, C. Sevensson, H. Hultberg, and G. Akusjarvi. 1987. A novel adenovirus-2 E1A mRNA encoding a protein with transcription activation properties. EMBO J. 62037-2044. [PMC free article] [PubMed]
130. Uversky, V. N., J. R. Gillespie, and A. L. Fink. 2000. Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41415-427. [PubMed]
131. van Ormondt, H., and B. Hesper. 1983. Comparison of the nucleotide sequences of early region E1b DNA of human adenovirus types 12, 7 and 5 (subgroups A, B and C). Gene 21217-226. [PubMed]
132. Velcich, A., and E. Ziff. 1988. Adenovirus E1a ras cooperation activity is separate from its positive and negative transcription regulatory functions. Mol. Cell. Biol. 82177-2183. [PMC free article] [PubMed]
133. Vousden, K. H., and P. S. Jat. 1989. Functional similarity between HPV16E7, SV40 large T and adenovirus E1a proteins. Oncogene 4153-158. [PubMed]
134. Wagner, J. A. 1999. Technology evaluation: tgDCC-E1A, targeted genetics/MD Anderson. Curr. Opin. Mol. Ther. 1266-270. [PubMed]
135. Wahlström, G. M., B. Vennstrom, and M. B. Bolin. 1999. The adenovirus E1A protein is a potent coactivator for thyroid hormone receptors. Mol. Endocrinol. 131119-1129. [PubMed]
136. Wan, J., W. Zhang, L. Wu, T. Bai, M. Zhang, K. W. Lo, Y. L. Chui, Y. Cui, Q. Tao, M. Yamamoto, S. Akira, and Z. Wu. 2006. BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol. Cell. Biol. 26448-456. [PMC free article] [PubMed]
137. Wang, H. G., E. Moran, and P. Yaciuk. 1995. E1A promotes association between p300 and pRB in multimeric complexes required for normal biological activity. J. Virol. 697917-7924. [PMC free article] [PubMed]
138. Ward, J. J., L. J. McGuffin, K. Bryson, B. F. Buxton, and D. T. Jones. 2004. The DISOPRED server for the prediction of protein disorder. Bioinformatics 202138-2139. [PubMed]
139. Webster, L. C., and R. P. Ricciardi. 1991. trans-Dominant mutants of E1A provide genetic evidence that the zinc finger of the trans-activating domain binds a transcription factor. Mol. Cell. Biol. 114287-4296. [PMC free article] [PubMed]
140. Webster, L. C., K. Zhang, B. Chance, I. Ayene, J. S. Culp, W. J. Huang, F. Y. Wu, and R. P. Ricciardi. 1991. Conversion of the E1A Cys4 zinc finger to a nonfunctional His2, Cys2 zinc finger by a single point mutation. Proc. Natl. Acad. Sci. USA 889989-9993. [PMC free article] [PubMed]
141. Whyte, P., K. J. Buchkovich, J. M. Horowitz, S. H. Friend, M. Raybuck, R. A. Weinberg, and E. Harlow. 1988. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334124-129. [PubMed]
142. Whyte, P., H. E. Ruley, and E. Harlow. 1988. Two regions of the adenovirus early region 1A proteins are required for transformation. J. Virol. 62257-265. [PMC free article] [PubMed]
143. Wong, H. K., and E. B. Ziff. 1994. Complementary functions of E1a conserved region 1 cooperate with conserved region 3 to activate adenovirus serotype 5 early promoters. J. Virol. 684910-4920. [PMC free article] [PubMed]
144. Xu, H. E., T. B. Stanley, V. G. Montana, M. H. Lambert, B. G. Shearer, J. E. Cobb, D. D. McKee, C. M. Galardi, K. D. Plunket, R. T. Nolte, D. J. Parks, J. T. Moore, S. A. Kliewer, T. M. Willson, and J. B. Stimmel. 2002. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. Nature 415813-817. [PubMed]
145. Yoo, G. H., M. C. Hung, G. Lopez-Berestein, S. LaFollette, J. F. Ensley, M. Carey, E. Batson, T. C. Reynolds, and J. L. Murray. 2001. Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent breast and head and neck cancer. Clin. Cancer Res. 71237-1245. [PubMed]
146. Zhang, W., H. M. Chan, Y. Gao, R. Poon, and Z. Wu. 2007. BS69 is involved in cellular senescence through the p53-p21Cip1 pathway. EMBO Rep. 8952-958. [PMC free article] [PubMed]
147. Zhang, X., A. S. Turnell, C. Gorbea, J. S. Mymryk, P. H. Gallimore, and R. J. Grand. 2004. The targeting of the proteasomal regulatory subunit S2 by adenovirus E1A causes inhibition of proteasomal activity and increased p53 expression. J. Biol. Chem. 27925122-25133. [PubMed]
148. Zhang, Z., M. M. Smith, and J. S. Mymryk. 2001. Interaction of the E1A oncoprotein with Yak1p, a novel regulator of yeast pseudohyphal differentiation, and related mammalian kinases. Mol. Biol. Cell 12699-710. [PMC free article] [PubMed]
149. Zhao, L. J., T. Subramanian, S. Vijayalingam, and G. Chinnadurai. 2007. PLDLS-dependent interaction of E1A with CtBP: regulation of CtBP nuclear localization and transcriptional functions. Oncogene 267544-7551. [PMC free article] [PubMed]
150. Zhao, L. J., T. Subramanian, Y. Zhou, and G. Chinnadurai. 2006. Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor CtBP2. J. Biol. Chem. 2814183-4189. [PubMed]

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