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GLI Genes and Their Targets in Epidermal Development and Disease

* and .

* Corresponding Author: Department of Molecular Biology, Division of Genomics, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria. Email: fritz.aberger@sbg.ac.at

Introduction

During the last decade an enormous wealth of data has been generated by many different laboratories showing that the Hedgehog (HH)/GLI signaling pathway plays key roles not only in the control of vertebrate embryonic development but also in adult organisms by regulating multiple biological processes such as cell differentiation, proliferation or programmed cell death. Interest in this signaling pathway further increased by the discovery that inappropriate activation of the pathway can be associated with the development of different cancer types, ranging from relatively harmless semi-malignant tumors of the skin such as Basal Cell Carcinoma (BCC) to highly aggressive and lethal malignancies of the brain, lung or gastrointestinal tract.1-3

In this chapter we focus on the role of the GLI zinc finger transcription factors as nuclear mediators of Hedgehog signaling in the epidermis and BCC. During epidermal development HH/GLI signal transduction has been implicated in the formation of hair follicles by controlling proliferation and morphogenesis. The pivotal role of this pathway in regulating cell division has been underlined by the finding that mutations causing constitutive activation of HH/GLI signaling can have fatal consequences and lead to the formation of BCC, the most common tumor in the western world.

First insight into how aberrant activation of HH/GLI signal transduction can trigger tumor formation came from genetic analysis of Gorlin (or NBCCS) syndrome, an autosomal dominant hereditary disease that predisposes patients to the early development of multiple BCCs. It was shown that BCCs of Gorlin patients as well as the majority of sporadic BCCs have inactivating mutations in Patched (PTCH), a twelve-pass transmembrane protein whose normal function is to suppress the pathway in the absence of HH ligand. As a result, the HH/GLI pathway becomes constitutively active in epidermal cells regardless of the presence of ligand.4-6 Furthermore, in a small fraction of sporadic BCC activating mutations have been identified in SMOH, a seven-pass transmembrane protein that acts downstream of PTCH and is essential for transduction of the HH-signal.7,8

The pivotal role of the pathway in BCC was further supported by a series of experiments carried out in different laboratories showing that sustained activation of HH-signaling in the epidermis and hair follicles by transgenic expression of either Sonic Hedgehog protein or downstream effectors such as an oncogenic form of SMOH or members of the GLI family of zinc finger transcription factors leads to the formation of BCC-like tumors in mice.7,9-12

Despite this clear understanding of the role of HH/GLI signaling in the initiation of BCC, numerous questions relating to the complex downstream mechanisms triggered by aberrant pathway activation remain to be answered. In particular, the oncogenic function of the zinc finger transcription factors and mediators of HH-signaling, GLI1 and GLI2, is not entirely understood. Both transcriptional regulators are highly expressed in BCCs and are able to induce epidermal tumorigenesis when overexpressed in the basal layer of mouse epidermis.10,12-14 But what transcriptional changes controlled by GLI1 and GLI2 underlie Hedgehog-induced carcinogenesis and what is their respective role in and relative contribution to tumor formation? Do they share redundant functions or do they control distinct biological properties by regulating different sets of target genes? How is their own expression regulated?

Although this chapter will not be able to answer these questions, the aim of the following sections will be to reconcile results from recent experiments on Hedgehog/GLI signaling in various biological contexts, to infer models of GLI function in epidermal development and disease and to outline future studies that will need to be done to understand in detail the molecular basis of HH-induced tumorigenesis.

GLI Genes and Epidermal Development

The role of HH/GLI signaling in vertebrate skin has been extensively studied during embryonic hair follicle formation. One of the first morphological signs of hair follicle development is the appearance of epidermal placodes induced by signals originating from specialized mesodermal cells underneath the placode and from adjacent epidermal cells. As a result, cells of the epidermal placode start to grow down into the dermal compartment of the skin, eventually forming the mature hair follicle, a process that requires reciprocal communication between epidermal and mesodermal cells (fig. 1A) (for review see ref. 15).

Figure 1. Role of GLI proteins in embryonic hair follicle development.

Figure 1

Role of GLI proteins in embryonic hair follicle development. A) Hair follicle development is initiated by reciprocal signaling between epidermal and underlying dermal cells leading to the formation of the epidermal placode that expresses Shh. Paracrine (more...)

Genetic analysis of mice lacking functional Sonic Hedgehog (Shh) protein revealed that Hedgehog/GLI signaling is essential for hair follicle morphogenesis. Epidermis of Shh -/- mice is still able to form placodes, which, however, do not develop significantly beyond this stage but arrest due to defects in proliferation and morphogenesis.16,17 Expression of Shh is first detected in the placode itself, while the Shh receptor Patched (Ptc) as well as the downstream effectors Gli1 and Gli2 are expressed in the placode and underlying mesodermal cells, suggesting autocrine as well as paracrine signaling in Shh-regulated hair follicle development.16

Recent experiments taking advantage of sophisticated transgenic and gene-targeting approaches have shed more light on the respective roles of Gli transcription factors in mediating Shh-signaling during hair follicle morphogenesis in mice. While Gli1 and Gli3 loss of function mutations do not affect hair development, Gli2 homozygous mutants, similar to Shh -/- mice, fail to grow hair follicles beyond the placode stage, suggesting that Gli2 is the major player in transducing the Shh-signal in the nucleus of responding cells (fig. 1B). Transgenic expression of wild-type Gli2 in the epidermis of Gli2 mutant mouse embryos could overcome the early arrest in hair follicle development and restored Shh-target gene expression and proliferation, showing that Gli2 function is required in the epidermis rather than in the underlying mesoderm. Strikingly, the ability of wild-type Gli2 to rescue the Gli2 -/- epidermal phenotype depended on the presence of functional Shh protein, which would be consistent with the conversion of murine Gli2 from an inactive to an active form by upstream signals initiated by Shh. Activation of mouse Gli2 protein may involve modification of the N-terminal region, since an N-terminal Gli2 deletion variant is constitutively active and does not depend on Shh-signaling.18,19 Whether a similar regulatory mechanism also applies to the human homologue is unclear at present, since the N-terminus of human GLI2 is substantially shorter than that of mouse Gli2. Furthermore, full-length human GLI2 is already a strong transcriptional activator comparable to GLI1, while mouse Gli2 is a much weaker activator unless the putative N-terminal repression domain is removed.14,19 A more detailed comparison of the activities of human and murine Gli2 proteins will therefore be important for understanding their functional properties in both normal and diseased tissues.

Human Epidermis and the Origin of BCC

One of the major functions of the multilayered epidermis is to protect the body against physical traumas and environmental damage caused by UV-irradiation or toxic substances. In addition to protective stratified epidermis, epidermal cells give rise to sebaceous glands, sweat glands and hair follicles that cyclically undergo phases of regression and regrowth. Epidermal cells have a relatively short lifetime. The continuous loss of cells from stratified epidermis and the cyclic growth and degeneration of hair follicles requires that these epidermal structures be maintained by a precise balance between cell proliferation, differentiation and cell loss or death, a process referred to as tissue homeostasis. Maintenance of the epidermis and its appendages throughout life is ensured by stem cells that are able to self-renew as well as to produce progeny termed transit amplifying cells that undergo several rounds of proliferation before differentiation20,21 (fig. 2A,B).

Figure 2. Tissue homeostasis in stratified human epidermis.

Figure 2

Tissue homeostasis in stratified human epidermis. A) Loss of cells from the cornified layer is compensated by rapid proliferation of transit amplifying cells (TA) in the basal layer. TAs are the progeny of stem cells (SC, red cell), destined to undergo (more...)

Epidermal stem cells have been shown to reside in the basal layer of the epidermis and in the bulge region of hair follicles. Consistent with their multipotent nature, stem cells are thought to contribute to all epidermal lineages. Given the relatively short lifetime of differentiated epidermal cells, long-lived stem cells and transit amplifying cells are considered likely targets of oncogenic mutations (fig. 3). Accumulation of mutations in these cells can lead to aberrant activation of signaling pathways that normally control proliferation and differentiation, eventually resulting in tumor formation.20,22,23

Figure 3. Hierarchical model of oncogenic mutations leading to BCC development.

Figure 3

Hierarchical model of oncogenic mutations leading to BCC development. Mutations in tumor suppressors or oncogenes are likely to occur in transit amplifying (TA) or long-lived epidermal stem cells (SC), resulting in tumor expansion by increased proliferation (more...)

Whether HH/GLI signaling is inappropriately activated in epidermal stem cells or in committed cells is unclear at present. BCCs present as poorly differentiated tumors that resemble in some aspects undifferentiated aberrant hair follicle-like structures, suggesting that BCCs could represent hair follicle derived tumors. Expression analysis of Hedgehog pathway components in normal hair follicles showed that Hedgehog-responsive genes including PTCH, GLI1 and GLI2 as well as the GLI targets FOXE1 and BCL2 are expressed in the Outer Root Sheath (ORS) of hair follicles, while SHH expression is restricted to the matrix region, which comprises proliferating cells.24-27 It therefore appears possible that BCCs derive from the ORS or possibly from the bulge region, where ligand-independent HH-signal transduction may cause increased proliferation at the expense of differentiation (fig. 3), a scenario that would be consistent with the biological activities of GLI genes.

Alternatively, BCC may also originate from the basal layer of interfollicular epidermis or even from cells that have already entered the differentiation pathway. Support for the latter comes from experiments showing that activation of oncogenes can reprogram post-mitotic, differentiated keratinocytes to undergo proliferation.28 In this context it is noteworthy that forced expression of the GLI2 oncogene in human epidermal cells in vitro is able to oppose differentiation signals and induce reentry into the cell cycle,29 suggesting that sustained HH-signaling is able to reactivate proliferation in differentiated cells of human epidermis (see fig. 4).

Figure 4. Model of GLI activation in BCC development.

Figure 4

Model of GLI activation in BCC development. Mutations resulting in loss of PTCH or gain of SMOH function (SMOH-A*) convert a latent inactive transcription factor - possibly GLI2 or GLI3 - into a strong activator form. Activated GLI2/3 directly induces (more...)

GLI1 and GLI2 in Basal Cell Carcinoma

Signal transduction pathways such as Wnt/wingless or Hedgehog have long been known to be important regulators of embryonic development. Over the last few years, however, it has become evident that grave consequences for the organism ensue from unscheduled activation of these pathways in later life. While in normal cells and tissues the activity of these pathways is restrained closely in space and time by the deployment of negative regulators, cells carrying mutations in these repressor genes may readily escape these control mechanisms and undergo uncontrolled proliferation.30

In a series of experiments carried out in different laboratories it has been shown that loss of the HH-pathway repressor PTCH results in constitutive, ligand-independent pathway activation, thereby triggering BCC development.4-6 As a result of ligand-independent HH-signaling in BCC, tumor cells express highly elevated levels of GLI1 and to a lesser extent also of GLI2, while GLI3 expression appears to be unchanged.13,14,31 Activation of GLI1 and GLI2 is thought to be responsible for the mediation of aberrant HH-signaling in the nucleus of epidermal cells and the activation of the oncogenic transcriptional program underlying BCC development. The oncogenicity of these transcription factors (TFs) has been demonstrated in transgenic mouse models, where the expression of both human GLI1 and murine Gli2 was directed to the basal layer of the epidermis by using a keratin5-promoter for transgene expression. Both TFs were able to induce epidermal tumors, though expression of full-length Gli2 mainly induced BCC-like structures, while GLI1 expression led to multiple types of epidermal cancer including trichoblastoma, trichoepithelioma and BCC-like tumors.10,12 The distinct phenotypes of the transgenic mice might be explained by the fact that murine Gli2 on its own is a relatively weak transcriptional activator that appears to require upstream HH-signaling in order to be converted into a strong inducer of Hh-targets genes.18,32,33 Given that in murine skin expression of Sonic Hedgehog is restricted to the hair follicle region, Gli2 would only become activated in the K5-transgenics in a sub-population of cells of the hair follicle (those that receive the Hh-signal), where it could promote the growth of BCC-like tumors with similarities to aberrant hair follicles. Consistent with this model, mice expressing a constitutively active form of Gli2 under control of the K5-promoter develop a broader spectrum of tumors similar to mice expressing GLI1.34

Although these experiments have provided valuable information on the identity of the nuclear transducers of oncogenic HH-signaling, the results also raise a number of questions. It is still unclear whether GLI1 and GLI2 have redundant functions or whether they accomplish distinct tasks in response to oncogenic HH-signaling, and if the latter is the case, how they regulate distinct sets of target genes. Are both GLI1 and GLI2 functions required for transducing oncogenic HH-signaling in the nucleus of responsive cells? If so, what is the relative contribution of these proteins to tumorigenesis? Answering these questions will be an important step towards defining the critical molecular events at the distal end of HH-signaling in tumor development.

The Oncogenic Nature of GLI Transcription Factors

Much of our current knowledge about how GLI transcription factors promote cellular transformation and tumorigenesis are based on studies of the GLI1 oncogene, which was first identified as a gene highly amplified in glioblastoma.35 GLI1 has been implicated in HH-associated cancer formation and/or maintenance by its ability to transform cells in combination with E1A, its tumor-inducing activity in mice and frogs when overexpressed in the epidermis and its high-level expression in tumors with increased HH-signaling.12,13,35-39 Furthermore, forced expression of GLI1 promotes proliferation of human epidermal cells in a cell-autonomous manner, probably by the direct regulation of genes involved in cell cycle progression.14,32,40

More recent genetic data, however, support a pivotal role for GLI2 in mediating HH-signaling in the epidermis and possibly in tumorigenesis. Like Shh, Gli2 function is essential for proper hair follicle formation, while Gli1 and Gli3 are dispensable for normal hair development.18 Gli1 is also not required for Shh-induced medulloblastoma formation, since brain tumors do develop in Gli1-/- mice in response to overexpression of Shh.41,42 Together with the finding that overexpression of Gli2 in mouse epidermis is sufficient to induce BCC-like tumors, these data raise the possibility that GLI2 rather than GLI1 may encode the critical factor, involved in executing oncogenic HH-signaling in response to constitutive pathway activation. Finding out whether loss of Gli2 function abrogates the ability of aberrant HH-signaling to induce tumors will allow greatly refined and clearer models of Hh-induced tumorigenesis to be constructed.

How might GLI genes promote epidermal cancer formation in response to aberrant HH-signaling? Like GLI1, GLI2 promotes proliferation of epidermal cells in the absence of dermal cells, suggesting that both transcription factors act cell-autonomously rather than by stimulating paracrine signals that in vivo may trigger the release of mitogenic stimuli from dermal cells.14,18 Insight into the molecular changes induced by an increase in GLI2 activity in human epidermal cells has come from DNA-array based gene expression studies. Expression of GLI2 in human keratinocytes induces a number of genes involved in G1-S phase and G2-M phase progression such as E2F, D-type cyclins, Cyclin A2, CDK1, and Cyclin B1.29 GLI genes may act directly at the heart of the cell cycle machinery. Analysis of the Cyclin D2 promoter revealed the presence of at least one Gli-binding site and experiments using cycloheximide to block protein synthesis in Shh-treated cells corroborated the notion that Cyclin D2 is a direct GLI target gene.32,40 Also, the rate of E2F1 mRNA accumulation in response to GLI2 is comparable to that of the direct GLI target PTCH, which suggests that E2F1—a transcription factor involved in the activation of S-phase genes in response to mitogenic stimuli—may be a direct GLI target gene like Cyclin D2.29 Studies in the fruit fly have identified Cyclin E as direct transcriptional target of the Drosophila homologue of vertebrate GLI genes, Cubitus interruptus, but it is not yet clear whether this also applies in mammalian systems.43

Not only can human GLI2 act as potent inducer of cell cycle progression genes, GLI2 has also been shown to antagonize epidermal differentiation signals. Expression of GLI2 in human keratinocytes led to repression of epidermal differentiation-associated genes under conditions that normally promote epidermal differentiation.29 Repression of differentiation-associated genes by GLI2 may point to a role as transcriptional repressor as has been proposed for Gli2 in vertebrate somite patterning.32 Alternatively, suppression of epidermal differentiation may be accomplished by activation of downstream repressors in response to GLI2. In this context it is noteworthy that GLI2 directly induces the expression of the forkhead transcription factor FOXE1, which has been shown to have repressor function and may therefore be a candidate mediator of at least part of the antagonistic effect of GLI2 on epidermal differentiation.44

A further mechanism likely to contribute to the oncogenic activity of GLI factors is the fact that transcription of the key anti-apoptotic factor BCL2 is directly controlled by GLI1 and GLI2.25,25a GLI1 has also been shown to directly stimulate the transcription of Snail1, a transcription factor promoting epithelial-mesenchymal transition (EMT) and invasive tumor growth.45 Another interesting connection has been established in Xenopus, where certain Wnt-signaling molecules are under the control of Gli factors and are required for the ventro-posteriorizing effect induced by Gli2 and Gli3. Consistent with a possible downstream role of Wnt factors in HH-induced carcinogenesis, Gli1-induced BCC-like tumors in frog and human BCCs contain elevated mRNA levels of various Wnt genes.46 By screening for signaling pathways that act downstream of HH/GLI it could be shown that proliferation of mouse BCC-like tumors involves activation of the ras-ERK pathway, possibly stimulated by activation of the PDGFR-alpha signaling cascade.47 Given the critical role of Wnt signaling and ras-ERK pathway activation in a variety of malignancies it is, therefore, likely that these signaling cascades mediate at least some aspects of BCC development downstream of HH-signaling.

In summary, the oncogenic activity of GLI1 and GLI2 in BCC is likely to rely on the manifold activities of GLI proteins: promoting cell cycle progression, activating growth-promoting signaling pathways, inhibiting epidermal proliferation, promoting cell survival by direct activation of BCL2 and inducing genes involved in tumor invasion (see fig. 4).

Regulation of GLI Expression

The regulation of the activity of vertebrate Gli transcription factors occurs at multiple levels and is still not completely understood.

Unlike the Drosophila Gli homologue Cubitus interruptus, which is primarily regulated at the post-translational level by proteolytic processing, vertebrate Gli genes are (also) regulated at the transcriptional level, where Gli1 and Gli2 are activated while Gli3 appears to be repressed in response to Hh-signaling. Similar to Drosophila Ci, Gli3 has been shown to encode a transcriptional repressor generated by proteolytic processing of the full-length protein in the absence of Hedgehog-signaling.33,48-51 To what extent Gli1 and/or Gli2 are regulated by proteolysis in vivo is not yet fully clear.

Transcriptional control of the GLI1 oncogene has recently been addressed by the analysis of cells mutant for different combinations of Gli transcription factors and by functional promoter studies. It was shown that the activation of Gli1 in response to Shh does not occur in the absence of Gli2.32 Consistently, mice lacking functional Gli2 protein display significantly reduced levels of Gli1, while overexpression of GLI2 in human keratinocytes rapidly induces GLI1 transcription.14,52 Analysis of the human GLI1 promoter identified a single Gli-binding site that is essential for activation by GLI2, showing that GLI1 transcription is directly regulated by GLI2.53 How then is transcriptional activation of Gli1 and also of Gli2 initiated in response to Hedgehog? Experiments using cycloheximide have shown that induction of Gli1 transcription in response to Shh does not depend on protein synthesis, indicating that the activating protein(s) for Gli1 transcription must already be present in the cell prior to activation of the Hh-pathway.32 Since Gli2 activator function appears to be dependent on Hedgehog-signaling,18 Gli2 protein itself and/or Gli3 could be the latent activator that induces Gli1 transcription as soon as the Hh-pathway is turned on, either by ligand binding or as in the case of BCC, by inactivation of PTCH (fig. 4).32

To clarify the regulation of GLI genes, it will be necessary to elucidate the molecular mechanism responsible for the conversion of the full-length Gli2 protein into a strong transcriptional activator in response to Hh-signaling and to address whether a similar mechanism applies to human GLI2, which lacks most of the N-terminal domain supposed to be required for keeping mouse Gli2 in a hypo-active state.

Induction of GLI2 transcription in response to Hh-signaling is only poorly understood at present. In particular, it is unclear whether the proposed latent Gli activator also directly induces Gli2 transcription in response to pathway activation. A possible mechanism by which high levels of GLI2 mRNA might be achieved in response to HH-signaling would be by activation of GLI1 itself. Expression of GLI1 in human epidermal cells has been shown to induce the expression of GLI2, indicating the existence of a positive feedback mechanism that may also operate in carcinogenesis and contribute to maintenance of high levels of both GLI1 and GLI2 (fig. 4).14 However, since loss of Gli1 function in mice does not appear to have a significant impact on the expression of Gli2, the in vivo relevance of the GLI1-GLI2 feedback remains to be addressed in future experiments.

Another mechanism involved in the regulation of Gli2 expression has been revealed by the analysis of mice homozygous mutant for Notch. Intriguingly, loss of Notch function in the epidermis led to an increase in Gli2 mRNA levels and to the development of BCC-like tumors, possibly as a consequence of elevated levels of Gli2.54 Expression of Gli2 therefore appears to be negatively regulated by Notch signaling (fig. 4). Detailed analysis of the Gli2 promoter will be an important prerequisite for the elucidation of the regulatory mechanisms involved in the control of Gli2 transcription.

Unresolved Problems and Future Perspectives

During the past years substantial progress has been made in understanding the involvement of the HH/GLI-signal transduction pathway in cancer and the details underlying the oncogenic activity of GLI genes are emerging but a number of unresolved issues remain. The target gene specificities of GLI genes are still not well defined. GLI proteins have a highly conserved DNA-binding domain consisting of 5 C2-H2 zinc fingers, which bind to the consensus Gli-binding site GACCACCCA.55 Despite the high conservation of the DNA-binding domain of GLI proteins, there is evidence that they regulate different target genes in similar biological contexts. In frogs, for instance, Gli2 but not Gli1 is involved in ventro-posterior mesodermal development downstream of FGF-signaling and only Gli2 but not Gli1 is able to directly control the expression of Xbra and Xhox3.56 Distinct activator specificities of Gli1 and Gli2 have also been observed by heterologous expression in Drosophila imaginal discs and by overexpression in murine presomitic mesodermal cells.32,33 It will be interesting to see whether all Gli genes bind their target sequences with comparable affinities or whether variations of the consensus Gli-binding site found in promoters of target genes result in subtle alterations of DNA-protein binding properties, which may account for the distinct specificities observed. Another question that needs to be addressed is whether distinct domain organization of GLI proteins contributes to distinct transcriptional read-out. For instance, a CBP-interacting domain was identified in Ci, GLI3 and based on sequence analysis, possibly also in GLI2 but not in GLI157-59 (and data not shown), suggesting that interactions with coactivators may change the transcriptional regulator activities of GLI proteins. In this context, a screen for factors that interact with Gli proteins would help understanding the different biological activities of these proteins. With respect to the oncogenic properties of GLI proteins, the identification of a larger number of GLI targets in different Hedgehog-associated tumors such as tumors of the gastrointestinal tract, the lung or the brain will be essential to elucidate the relative contribution of GLI proteins to Hedgehog-induced tumorigenesis. These experiments will also allow addressing the question of whether there exists a common theme at the transcriptional level in GLI-induced tumorigenesis or whether the response of a cell to oncogenic HH/GLI signaling is mainly dependent on the cell type and the biological context.

Given the pivotal role of GLI transcription factors in executing aberrant Hedgehog signaling in cancer, targeted inactivation of these factors may hold promise for future therapeutic approaches, complementary to current approaches that involve systemic and sustained administration of specific inhibitors of the Hedgehog signal transducer Smoothened.38,39,60,61 Such approaches may rely on stable repression of GLI expression by RNA interference62 or on the administration of decoy oligonucleotides, which have been designed to specifically block the activity of a given transcription factor (for reviews see refs. 63, 64). A more detailed understanding of the regulation and the activity of GLI proteins in disease should accelerate the development of novel anti-cancer strategies in the future.

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