Logo of ccLink to Publisher's site
Cell Cycle. 2011 Nov 15; 10(22): 3849–3852.
Published online 2011 Nov 15. doi:  10.4161/cc.10.22.18329
PMCID: PMC3356804

The expanding relevance of nuclear mTOR in carcinogenesis


Deregulated mTOR signaling drives the growth of various human cancers, making mTOR a major target for development of cancer chemotherapeutics. The role of mTOR in carcinogenesis is thought to be largely a consequence of its activity in the cytoplasm, resulting in increased translation of pro-tumorigenic genes. However, emerging data locate mTOR in various subcellular compartments, including Golgi, mitochondria, endoplasmic reticulum and the nucleus, implying the presence of compartment-specific mTOR substrates and functions. Efforts to identify mTOR substrates in these compartments and the mechanisms by which mTOR recruits these substrates and affects downstream cellular processes will add to our understanding of the diversity of roles played by mTOR in carcinogenesis.

Key words: mTOR, TOS motifs, mTORC1, nuclear substrates, cell survival, cancer, SIRT1, epigentic regulation, transcription regulation, chromatin modification

Mammalian target of rapamycin, mTOR, is a PI3K-related Ser/Thr kinase that regulates cell growth, proliferation and survival by integrating various external signals into intracellular machinery via two known mTOR-containing complexes, mTOR complex 1 (mTORC1) and mTORC2.1,2 Aberrant mTOR signaling is often associated with human cancers3 and is implicated in a wide range of pathogenic conditions and processes, including metabolic diseases, epileptogenesis and aging.1,4,5 Because of its primary role in translation, mTOR has been viewed as an exclusively cytoplasmic protein. However, this view is changing as a result of emerging data showing that mTOR resides in numerous cellular compartments, including the Golgi apparatus,6,7 the endoplasmic reticulum,7,8 the mitochondrial outer membrane,9 lysosomes10 and the nucleus.1114 Compartment-dependent substrate specificity and functions have been shown; for example, mTORC1 has been shown to directly interact with YY1, a zinc-finger GLI-Kruppel class of transcription factor that regulates the expression of mitochondrial genes.15 Inhibition of mTOR leads to defective YY1 activation and interaction with PGC-1α (peroxisome-proliferator-activated receptor coactivator), which then inhibits the transcriptional control of mitochondrial oxidative function.15 mTOR has also been shown to accumulate at a specific location in Golgi together with autophagic components during Rasinduced senescence, a phenomenon that was shown to be associated with interleukin-6/8 synthesis.6 The upstream signals and mechanisms leading to the spatial arrangement of mTOR, the functions of mTOR in these cellular compartments and whether mTOR forms complexes distinct from mTORC1 and mTORC2 are all yet to be fully understood. Clearly, identification of new compartment-specific mTOR substrates will expand our view of the functional diversity of mTOR signaling.

mTOR and its Nuclear Activities: A Link to Epigenetic Regulation of Cancer Cell Survival

The nuclear activities of mTOR have been associated with increases in its cytoplasmic functions in the control of protein translation.16 Shuttling of mTOR between cytosol and the nucleus has been shown to increase its kinase capacity in the cytoplasm.13,17 mTOR binding to the promoters of rDNA (rDNA) and tRNA (tRNA) genes have been shown to increase protein biosynthetic capacity.16 mTOR was also shown to interact with TFIIIC, a transcription factor that binds to pol III promoters.18 Binding of mTOR to TFIIIC may allow tRNA and 5S rRNA expression, resulting in enhanced protein synthesis in response to nutrients and growth factors.18 In another example, sequestration of mTOR in the nucleus through physical interaction with promyelocytic leukemia protein (PML) has been shown to suppress the synthesis rate of hypoxia-inducible factor 1α (HIF-1α).19 However, accumulating data indicate additional role(s) of mTOR in the nucleus. A potential link between mTOR signaling and increased mutagenesis was shown in a yeast system in which TOR signaling is required for S-phase progression and yeast cell survival in response to genotoxic stress.20 Levels of dNTPs have been shown to increase following DNA damage, and this increase, which is necessary for the function of error-prone translesion DNA polymerases,20 dramatically promotes cell survival—at the cost, however, of an increased mutation rate.21 Thus, it is postulated that increased mutation rates accompanying TOR-dependent cell survival in response to DNA damaging agents may contribute to the acquisition of chemotherapeutic drug resistance.20 Given the current recognition that there are significant levels of nuclear mTOR in cancer cells,12 this has important implications in cancers where chemoresistance is a major impediment to successful treatment outcomes. The question is, does nuclear mTOR activity correlate with chemoresistant cancer cell survival? Using A431 human squamous cell carcinoma (SCC) cells, we recently demonstrated that DNA damage-induced nuclear mTOR signaling, via inhibitory phosphorylation of Sirtuin 1 (SIRT1), a NAD-dependent deacetylase, mediates chemoresistant cell survival.22 The direct phosphorylation-dependent inhibition of SIRT1 by mTOR increases expression of the anti-apoptotic Bcl-2 family member, Bfl-1/A1, via increased p65 NFκB acetylation, which renders cells resistant to DNA damage-induced apoptosis.22 SIRT1 forms complexes with mTORC1 in response to treatment with genotoxic agents (Fig. 1);22 furthermore, this complex is persistently sustained in chemoresistant variants of A431 cells (Fig. 2). The formation of mTORC1-SIRT1 complexes, mTORC1-mediated signaling and the resulting apoptosis resistance are blocked in the presence of rapamycin (Figs. 1 and and22). It is of interest that nuclear mTORC1 signaling is associated with a p53-independent premature senescence-like cell cycle arrest in A431 cells.22 mTOR activation was recently shown to favor senescence in p53-arrested cells by fostering the ongoing cell growth in the arrested cells, while inhibition of mTOR leads to quiescence.23 However, in response to genotoxic stress, cells that are deficient in p53 and already have active cytoplasmic mTOR signaling, as in the case of A431 cells, may transition from an mTOR-regulated growth state to a survival state. We show, in A431 cells, that this transition requires the nuclear translocation of cytoplasmic mTOR.22 Given the nuclear activities of mTOR in the control of protein biosynthetic capacity,16 it remains to be elucidated whether nuclear mTORC1 signaling regulates, in part, senescence induction. Furthermore, p53-deficient human colon cancer cells were shown to have increased resistance and anchorage-independent growth upon mTOR activation, which involved the activation of a DNA damage response,24 raising questions regarding the cellular consequences of genotoxic stress and mTOR activation—cytoplasmic vs. nuclear—and whether nuclear mTORC1 signaling requires a p53-independent environment. Moreover, SIRT1 deacetylates diverse proteins, including histones, transcription factors and cofactors. Whether persistent mTORC1-dependent repression of SIRT1 deacetylase leads to broad modifications in chromatin function through acetylation of histones as well as by promoting alterations in the methylation of histones and DNA are important issues to be addressed. It is noteworthy that mTOR has been shown to form a functional transcriptional complex with CBP/p300, a coactivator of HIF-1α, leading to increased transcriptional activity of HIF-1α.25 mTOR has also been shown to bind to the promoters of RNA polymerase I- and III-transcribed genes in β-TC6 cells.26 These data suggest that mTOR may have specific roles in gene regulation, and that proteins and substrates with which mTOR interacts may play functional roles in mediating epigenetic modifications.

Figure 1
Inhibition of DNA damage-induced formation of mTOR-SIRT1 complex by rapamycin in A431 cells. Direct detection of nuclear mTOR-pS47 SIRT1 complexes in response to genotoxic agents (DOX, doxorubicin, 1 µM; CIS, cisplatin, 20 µM) and in the ...
Figure 2
Sustained mTOR-SIRT1 complexes in chemoresistant A431 variants. Chemoresistant A431 clones (DR6 and DR7) derived from A431 cells treated with 1 µM DOX for 48 h then cultured in the absence of DOX for >30 d have reduced SIRT 1 activity ...

Putative Nuclear Substrates Identified by TOS Motif

Perhaps the most important structural element in the cellular processes mediated by mTORC1 signaling is a highly conserved TOS (TOR signaling) motif present in mTOR substrates. mTORC1 consists of mTOR, raptor and mLst8/GβL. The TOS motif allows substrates to bind to mTOR through raptor.27,28 The TOS motif is present in known mTOR substrates, such as S6K1, 4EBP1 and HIF-1α25,2729. In addition to SIRT1,22 STAT3 (signal transducer and activator of transcription 3) is also known to contain two putative TOS motifs, although the importance of these has not been confirmed experimentally.30 Identification of new mTOR substrates in the nucleus will likely reveal additional role(s) of mTOR in the nucleus. A search of the protein sequence database for proteins containing known variations of TOS motifs (FDVEL, FDIEL, FEMDI, FEMDV, FDIDL, FDVDL, FEIDL) identified 39 candidates containing at least one TOS motif. These include proteins located in various subcellular structures including the cell membrane, endoplasmic reticulum and mitochondria as well as secreted proteins. Table 1 shows a list of candidates localized in the nucleus. A majority are proteins involved in transcription regulation and epigenetic modification; they include hEaf6, JARID1B (KDM5B/PLU-1/RBP2-H1) and ATF6α. hEaf6 is a component of HBO1 HAT complex, which is likely responsible for the majority of histone H4 acetylation, and plays key roles in gene regulation and DNA replication.31 JARID1B (KDM5B/PLU-1/RBP2-H1) is a member of the highly conserved family of jumonji/ARID1 (JARID1) histone 3 K4 (H3K4) demethylases and was recently shown to be essential for continuous melanoma growth.32 ATF6α is a transcription factor essential for the adaptation of dormant cells to chemotherapy and nutritional stress. It was recently shown to be critical for survival of quiescent squamous carcinoma cells via the ATF6α-Rheb-mTOR pathway.33 Interestingly, three putative mTOR phosphorylation sites are present in ATF6α (Table 1), suggesting possible translational modification of ATF6α by mTORC1. The physical interaction between these proteins and mTORC1, specifically with raptor, needs further investigation. Furthermore, studies into the functional implication of these interactions will be important for our appreciation of the full engagement of mTORC1 in various cellular activities, such as chromatin modification, transcription regulation, metabolism, hypoxia and regulation of cell cycle progression, all of which contribute to the relevance of mTOR in carcinogenesis.

Table 1
Nuclear proteins containing putative TOS motifs


This work was partially supported by Irving Scholar Award and 5P30 ES009089.


1. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21–35. doi: 10.1038/nrm3025. [PMC free article] [PubMed] [Cross Ref]
2. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22. doi: 10.1016/j.ccr.2007.05.008. [PubMed] [Cross Ref]
3. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011;121:1231–1241. doi: 10.1172/JCI44145. [PMC free article] [PubMed] [Cross Ref]
4. Pani G. P66SHC and ageing: ROS and TOR? Aging (Albany NY) 2010;2:514–518. [PMC free article] [PubMed]
5. Zeng LH, McDaniel S, Rensing NR, Wong M. Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): a double-edged sword? Cell Cycle. 2010;9:2281–2285. doi: 10.4161/cc.9.12.11866. [PMC free article] [PubMed] [Cross Ref]
6. Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science. 2011;332:966–970. doi: 10.1126/science.1205407. [PMC free article] [PubMed] [Cross Ref]
7. Drenan RM, Liu X, Bertram PG, Zheng XF. FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. J Biol Chem. 2004;279:772–778. doi: 10.1074/jbc.M305912200. [PubMed] [Cross Ref]
8. Liu X, Zheng XF. Endoplasmic reticulum and Golgi localization sequences for mammalian target of rapamycin. Mol Biol Cell. 2007;18:1073–1082. doi: 10.1091/mbc.E06-05-0406. [PMC free article] [PubMed] [Cross Ref]
9. Desai BN, Myers BR, Schreiber SL. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA. 2002;99:4319–4324. doi: 10.1073/pnas.261702698. [PMC free article] [PubMed] [Cross Ref]
10. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids. Cell. 2010;141:290–303. doi: 10.1016/j.cell.2010.02.024. [PMC free article] [PubMed] [Cross Ref]
11. Wang X, Proud CG. mTORC1 signaling: what we still don't know. J Mol Cell Biol. 2011;3:206–220. doi: 10.1093/jmcb/mjq038. [PubMed] [Cross Ref]
12. Zhang X, Shu L, Hosoi H, Murti KG, Houghton PJ. Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. J Biol Chem. 2002;277:28127–28134. doi: 10.1074/jbc.M202625200. [PubMed] [Cross Ref]
13. Bachmann RA, Kim JH, Wu AL, Park IH, Chen J. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem. 2006;281:7357–7363. doi: 10.1074/jbc.M512218200. [PubMed] [Cross Ref]
14. Wei Y, Zheng XFS. TORC1 association with rDNA chromatin as a mechanism to co-regulate Pol I and Pol III. Cell Cycle. 2009;8:3802–3803. doi: 10.4161/cc.8.23.10039. [PubMed] [Cross Ref]
15. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1[agr] transcriptional complex. Nature. 2007;450:736–740. doi: 10.1038/nature06322. [PubMed] [Cross Ref]
16. Jiang Y. mTOR goes to the nucleus. Cell Cycle. 2010;9:868. doi: 10.4161/cc.9.5.11070. [PubMed] [Cross Ref]
17. Park IH, Bachmann R, Shirazi H, Chen J. Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem. 2002;277:31423–31429. doi: 10.1074/jbc.M204080200. [PubMed] [Cross Ref]
18. Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci USA. 2010;107:11823–11828. doi: 10.1073/pnas.1005188107. [PMC free article] [PubMed] [Cross Ref]
19. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, et al. PML inhibits HIF-1[alpha] translation and neoangiogenesis through repression of mTOR. Nature. 2006;442:779–785. doi: 10.1038/nature05029. [PubMed] [Cross Ref]
20. Shen C, Lancaster CS, Shi B, Guo H, Thimmaiah P, Bjornsti MA. TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol. 2007;27:7007–7017. doi: 10.1128/MCB.00290-07. [PMC free article] [PubMed] [Cross Ref]
21. Chabes A, Georgieva B, Domkin V, Zhao X, Rothstein R, Thelander L. Survival of DNA Damage in Yeast Directly Depends on Increased dNTP Levels Allowed by Relaxed Feedback Inhibition of Ribonucleotide Reductase. Cell. 2003;112:391–401. doi: 10.1016/S0092-8674(03)00075-8. [PubMed] [Cross Ref]
22. Back JH, Rezvani HR, Zhu Y, Guyonnet-Duperat V, Athar M, Ratner D, et al. Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1. J Biol Chem. 2011;286:19100–19108. doi: 10.1074/jbc.M111.240598. [PMC free article] [PubMed] [Cross Ref]
23. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging (Albany NY) 2010;2:344–352. [PMC free article] [PubMed]
24. Rodríguez-Jiménez FJ, Moreno-Manzano V, Mateos-Gregorio P, Royo I, Erceg S, Murguia JR, et al. FM19G11: A new modulator of HIF that links mTOR activation with the DNA damage checkpoint pathways. Cell Cycle. 2010;9:2803–2813. doi: 10.4161/cc.9.14.12250. [PubMed] [Cross Ref]
25. Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem. 2007;282:20534–20543. doi: 10.1074/jbc.M611782200. [PubMed] [Cross Ref]
26. Tsang CK, Liu H, Zheng XFS. mTOR binds to the promoters of RNA polymerase I- and -III transcribed genes. Cell Cycle. 2010;9:953–957. doi: 10.4161/cc.9.5.10876. [PMC free article] [PubMed] [Cross Ref]
27. Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol. 2002;12:632–639. doi: 10.1016/S0960-9822(02)00762-5. [PubMed] [Cross Ref]
28. Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol. 2003;13:797–806. doi: 10.1016/S0960-9822(03)00329-4. [PubMed] [Cross Ref]
29. Lee VH, Healy T, Fonseca BD, Hayashi A, Proud CG. Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1. FEBS J. 2008;275:2185–2199. doi: 10.1111/j.1742-4658.2008.06372.x. [PubMed] [Cross Ref]
30. Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signal. 2009;21:827–835. doi: 10.1016/j.cell-sig.2009.01.012. [PubMed] [Cross Ref]
31. Saksouk N, Avvakumov N, Champagne KS, Hung T, Doyon Y, Cayrou C, et al. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol Cell. 2009;33:257–265. doi: 10.1016/j.molcel.2009.01.007. [PMC free article] [PubMed] [Cross Ref]
32. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010;141:583–594. doi: 10.1016/j.cell.2010.04.020. [PMC free article] [PubMed] [Cross Ref]
33. Schewe DM, Aguirre-Ghiso JA. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci USA. 2008;105:10519–10524. doi: 10.1073/pnas.0800939105. [PMC free article] [PubMed] [Cross Ref]

Articles from Cell Cycle are provided here courtesy of Landes Bioscience
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...