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.
Keywords
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Levine AJ, Hu W, Feng Z (2006) The p53 pathway: what questions remain to be explored? Cell Death Differ 13(6):1027–1036
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
Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506
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
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
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
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
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
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
Jacks T, Remington L, Williams BO et al (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4(1):1–7
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
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
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
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
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
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
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
Matoba S, Kang JG, Patino WD et al (2006) p53 regulates mitochondrial respiration. Science 312(5780):1650–1653
Bensaad K, Tsuruta A, Selak MA et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107–120
Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450(7170):721–724
Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365
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
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
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
Yoo L, Chung D, Yuan J (2002) LKB1-A master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2:529–535
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
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
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
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
Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159
Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18(6):598–608
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899
Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314
Elstrom RL, Bauer DE, Buzzai M et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64(11):3892–3899
Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24(50):7435–7442
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
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
Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732
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
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
Kondoh H, Lleonart ME, Gil J et al (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65(1):177–185
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
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
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
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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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