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The Regulation of the IGF-1/mTOR Pathway by the p53 Tumor Suppressor Gene Functions

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mTOR Pathway and mTOR Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The tumor suppressor p53 plays an important role in maintaining genomic stability and tumor prevention by responding to a wide variety of stress signals and initiating a transcriptional program to produce several different cellular responses. These stress signals all interfere with the cellular homeostatic mechanisms that monitor and control the fidelity of DNA replication, chromosome segregation, and cell division. The IGF-1 and mTOR pathways regulate cell growth and division and coordinate it with nutrient availability and energy demands during both development and throughout the life span of the organism. To protect cells from errors introduced into both cell growth and division by such stress signals, p53 negatively regulates the IGF-1/mTOR pathways. In this chapter the mechanisms that coordinate the regulation between p53 and IGF-1/mTOR pathways are presented. The impact of the p53 pathway upon glycolysis and oxidative phosphorylation, ribosomal and mitochondrial biogenesis, and autophagy are explored.

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References

  1. Levine AJ, Hu W, Feng Z (2006) The p53 pathway: what questions remain to be explored? Cell Death Differ 13(6):1027–1036

    Article  PubMed  CAS  Google Scholar 

  2. Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5(1):3–8

    Article  PubMed  CAS  Google Scholar 

  3. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506

    Article  PubMed  CAS  Google Scholar 

  4. Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D (1999) Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 96(26):14973–14977

    Article  PubMed  CAS  Google Scholar 

  5. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Genet 1(1):45–49

    Article  PubMed  CAS  Google Scholar 

  6. Harris S, Gil G, Robins H et al (2005) Detection of functional single-nucleotide polymorphisms that affect apoptosis. Proc Natl Acad Sci USA 102(45):16297–16302

    Article  PubMed  CAS  Google Scholar 

  7. Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res 66(9):4795–4801

    Article  PubMed  CAS  Google Scholar 

  8. Feng Z, Hu W, de Stanchina E et al (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67(7):3043–3053

    Article  PubMed  CAS  Google Scholar 

  9. Donehower LA, Harvey M, Slagle BL et al (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366):215–221

    Article  PubMed  CAS  Google Scholar 

  10. Jacks T, Remington L, Williams BO et al (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4(1):1–7

    Article  PubMed  CAS  Google Scholar 

  11. Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238

    Article  PubMed  CAS  Google Scholar 

  12. Bond GL, Hu W, Bond EE et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602

    Article  PubMed  CAS  Google Scholar 

  13. Bond GL, Hirshfield KM, Kirchhoff T et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110

    Article  PubMed  CAS  Google Scholar 

  14. Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM (2004) Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304(5670):596–600

    Article  PubMed  CAS  Google Scholar 

  15. Passer BJ, Nancy-Portebois V, Amzallag N et al (2003) The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase. Proc Natl Acad Sci USA 100(5):2284–2289

    Article  PubMed  CAS  Google Scholar 

  16. Amzallag N, Passer BJ, Allanic D et al (2004) TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J Biol Chem 279(44):46104–46112

    Article  PubMed  CAS  Google Scholar 

  17. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102(23):8204–8209

    Article  PubMed  CAS  Google Scholar 

  18. Matoba S, Kang JG, Patino WD et al (2006) p53 regulates mitochondrial respiration. Science 312(5780):1650–1653

    Article  PubMed  CAS  Google Scholar 

  19. Bensaad K, Tsuruta A, Selak MA et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107–120

    Article  PubMed  CAS  Google Scholar 

  20. Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450(7170):721–724

    Article  PubMed  CAS  Google Scholar 

  21. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365

    Article  PubMed  CAS  Google Scholar 

  22. Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868

    Article  PubMed  CAS  Google Scholar 

  23. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3(11):973–982

    Article  PubMed  CAS  Google Scholar 

  24. Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20(3):267–275

    Article  PubMed  CAS  Google Scholar 

  25. Yoo L, Chung D, Yuan J (2002) LKB1-A master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2:529–535

    Article  PubMed  CAS  Google Scholar 

  26. Shaw R, Kosmatka M, Bardeesy N et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101:3329–3335

    Article  PubMed  CAS  Google Scholar 

  27. Crighton D, Wilkinson S, O’Prey J et al (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126(1):121–134

    Article  PubMed  CAS  Google Scholar 

  28. Lum JJ, Bauer DE, Kong M et al (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120(2):237–248

    Article  PubMed  CAS  Google Scholar 

  29. Kong M, Fox CJ, Mu J et al (2004) The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306(5696):695–698

    Article  PubMed  CAS  Google Scholar 

  30. Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159

    Article  PubMed  CAS  Google Scholar 

  31. Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18(6):598–608

    Article  PubMed  CAS  Google Scholar 

  32. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899

    Article  PubMed  CAS  Google Scholar 

  33. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  PubMed  CAS  Google Scholar 

  34. Elstrom RL, Bauer DE, Buzzai M et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64(11):3892–3899

    Article  PubMed  CAS  Google Scholar 

  35. Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24(50):7435–7442

    Article  PubMed  CAS  Google Scholar 

  36. Shim H, Dolde C, Lewis BC et al (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94(13):6658–6663

    Article  PubMed  CAS  Google Scholar 

  37. Osthus RC, Shim H, Kim S et al (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275(29):21797–21800

    Article  PubMed  CAS  Google Scholar 

  38. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  PubMed  CAS  Google Scholar 

  39. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197

    Article  PubMed  CAS  Google Scholar 

  40. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185

    Article  PubMed  Google Scholar 

  41. Kondoh H, Lleonart ME, Gil J et al (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65(1):177–185

    PubMed  CAS  Google Scholar 

  42. Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64(7):2627–2633

    Article  PubMed  CAS  Google Scholar 

  43. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434

    Article  PubMed  CAS  Google Scholar 

  44. Mathupala SP, Ko YH, Pedersen PL, Hexokinase II (2006) cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25(34):4777–4786

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Radiation Cancer Biology, UMDNJ-Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA

    Zhaohui Feng

  2. School of Natural Sciences, Institute for Advanced Study, Princeton, NJ, 08540, USA

    Arnold J. Levine

Authors
  1. Zhaohui Feng
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  2. Arnold J. Levine
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Corresponding author

Correspondence to Arnold J. Levine .

Editor information

Editors and Affiliations

  1. Dept. Family Medicine, University of Minnesota, Minneapolis, 55455, USA

    Vitaly A. Polunovsky

  2. Director, Center for Childhood Cancer, Nationwide Children’s Hospital, The Research Institute, 700 Children’s Drive 332, Columbus, 43205, USA

    Peter J. Houghton

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Feng, Z., Levine, A.J. (2009). The Regulation of the IGF-1/mTOR Pathway by the p53 Tumor Suppressor Gene Functions. In: Polunovsky, V., Houghton, P. (eds) mTOR Pathway and mTOR Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-271-1_2

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  • DOI: https://doi.org/10.1007/978-1-60327-271-1_2

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-270-4

  • Online ISBN: 978-1-60327-271-1

  • eBook Packages: MedicineMedicine (R0)

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