p53, ARF, and the Control of Autophagy

Part of the Current Cancer Research book series (CUCR)


The p53 and ARF genes encode well-known tumor suppressor proteins that respond to oncogenic and genotoxic signals in order to induce growth arrest or apoptosis. Recently, both of these proteins were found to be intimately tied to metabolic pathways and to play surprising roles in autophagy. Autophagy (“self-eating”) is a critical response of eukaryotic cells to stress. During this process, portions of the cytosol, including cytoplasmic organelles, are sequestered into characteristic double-membrane vesicles called autophagosomes that are delivered to the lysosome for degradation. This rather non-specific degradation process allows the cell to adapt to its bioenergetic needs and to prolong survival. The following sections will outline the evidence for a role of p53 and ARF in autophagy, the role of this pathway in cancer, and what questions remain to be answered.


Endoplasmic Reticulum Stress Genotoxic Stress Mouse Embryo Fibroblast Sarcoma Cell Line Induce Cell Growth Arrest 


  1. Abida WM, Gu W (2008) p53-dependent and independent activation of autophagy by ARF. Cancer Res 68: 352–357.CrossRefPubMedGoogle Scholar
  2. Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134: 451–460.CrossRefPubMedGoogle Scholar
  3. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67: 6745–6752.CrossRefPubMedGoogle Scholar
  4. Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126: 121–134.CrossRefPubMedGoogle Scholar
  5. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13: 2658–2669.CrossRefPubMedGoogle Scholar
  6. Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ (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: 3043–3053.CrossRefPubMedGoogle Scholar
  7. 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: 8204–8209.CrossRefPubMedGoogle Scholar
  8. Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7: 667–677.CrossRefPubMedGoogle Scholar
  9. Humbey O, Pimkina J, Zilfou JT, Jarnik M, Dominguez-Brauer C, Burgess DJ, Eischen CM, Murphy ME (2008) The ARF tumor suppressor can promote the progression of some tumors. Cancer Res 68: 9608–9613.CrossRefPubMedGoogle Scholar
  10. Itahana K, Zhang Y (2008) Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell 13: 542–553.CrossRefPubMedGoogle Scholar
  11. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293.CrossRefPubMedGoogle Scholar
  12. Kelly-Spratt KS, Gurley KE, Yasui Y, Kemp CJ (2004) p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways. PLoS Biol 2: E242.CrossRefPubMedGoogle Scholar
  13. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N et al. (2007) Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26: 2527–2539.CrossRefPubMedGoogle Scholar
  14. Morselli E, Tasdemir E, Maiuri MC, Galluzzi L, Kepp O, Criollo A, Vicencio JM, Soussi T, Kroemer G (2008) Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell Cycle 7: 3056–3061.PubMedGoogle Scholar
  15. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.CrossRefPubMedGoogle Scholar
  16. Pimkina J, Humbey O, Zilfou JT, Jarnik M, Murphy ME (2009) ARF induces autophagy by virtue of interaction with and inhibition of Bcl-xl. J Biol Chem 284: 2803–2810.CrossRefPubMedGoogle Scholar
  17. Pimkina J, Murphy ME (2009) Arf, autophagy and tumor suppression. Autophagy 5: 1–3.CrossRefGoogle Scholar
  18. Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83: 993–1000.CrossRefPubMedGoogle Scholar
  19. Reef S, Kimchi A (2008) Nucleolar p19ARF, unlike mitochondrial smARF, is incapable of inducing p53-independent autophagy. Autophagy 4: 866–869.PubMedGoogle Scholar
  20. Reef S, Shifman O, Oren M, Kimchi A (2007) The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein. Oncogene 26: 6677–6683.CrossRefPubMedGoogle Scholar
  21. Reef S, Zalckvar E, Shifman O, Bialik S, Sabanay H, Oren M, Kimchi A (2006) A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell 22: 463–475.CrossRefPubMedGoogle Scholar
  22. Sherr CJ, Bertwistle D, Den Besten W, Kuo ML, Sugimoto M, Tago K, Williams RT, Zindy F, Roussel MF (2005) p53-dependent and -independent functions of the Arf tumor suppressor. Cold Spring Harb Symp Quant Biol 70: 129–137.CrossRefPubMedGoogle Scholar
  23. Sugimoto M, Kuo ML, Roussel MF, Sherr CJ (2003) Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol Cell 11: 415–424.CrossRefPubMedGoogle Scholar
  24. Tago K, Chiocca S, Sherr CJ (2005) Sumoylation induced by the Arf tumor suppressor: a p53-independent function. Proc Natl Acad Sci USA 102: 7689–7694.CrossRefPubMedGoogle Scholar
  25. Tasdemir E, Chiara Maiuri M, Morselli E, Criollo A, D’Amelio M, Djavaheri-Mergny M, Cecconi F, Tavernarakis N, Kroemer G (2008b) A dual role of p53 in the control of autophagy. Autophagy 4: 810–814.PubMedGoogle Scholar
  26. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, Criollo A, Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio JM, Carnuccio R, Moll UM, Madeo F, Paterlini-Brechot P, Rizzuto R, Szabadkai G, Pierron G, Blomgren K, Tavernarakis N, Codogno P, Cecconi F, Kroemer G (2008a) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10: 676–687.CrossRefPubMedGoogle Scholar
  27. Tasdemir E, Maiuri MC, Orhon I, Kepp O, Morselli E, Criollo A, Kroemer G (2008c) p53 represses autophagy in a cell cycle-dependent fashion. Cell Cycle 7: 3006–3011.PubMedGoogle Scholar
  28. Tavernarakis N, Pasparaki A, Tasdemir E, Maiuri MC, Kroemer G (2008) The effects of p53 on whole organism longevity are mediated by autophagy. Autophagy 4: 870–873.PubMedGoogle Scholar
  29. Ueda Y, Koya T, Yoneda-Kato N, Kato JY (2008) Small mitochondrial ARF (smARF) is located in both the nucleus and cytoplasm, induces cell death, and activates p53 in mouse fibroblasts. FEBS Lett 582: 1459–1464.CrossRefPubMedGoogle Scholar
  30. Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP (2000) p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev 14: 2358–2365.CrossRefPubMedGoogle Scholar
  31. Yee KS, Wilkinson S, James J, Ryan KM, Vousden KH (2009) PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ 16: 1135–1145.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Program in Molecular and Translational MedicineFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations