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. 2007 May 1;8(4):423–431. doi: 10.1111/j.1582-4934.2004.tb00467.x

HIF‐1 and p53: communication of transcription factors under hypoxia

Tobias Schmid 1, Jie Zhou 1, Bernhard Brüne 1,✉
PMCID: PMC6740063  PMID: 15601571

Abstract

Oxygen sensing and reactivity to changes in the concentration of oxygen is a fundamental property of cell physiology. The lack of O2 (hypoxia) is transmitted into many adaptive responses, a process that is largely controlled by a transcription factor known as hypoxia inducible factor‐1 (HIF‐1). More recent reports suggest that besides its traditional regulation via proteasomal degradation other signaling pathways contribute to stability regulation of the HIF‐1α subunit and/or HIF‐1 transactivation. These regulatory circuits allow for the integration of HIF‐1 into scenarios of cell‐survival vs. cell‐death with the rule of the thumb that short‐term mild hypoxia maintains cell viability while prolonged and severe hypoxia provokes cell demise. Cell death pathways are associated with stabilization of the tumor suppressor p53, a response also seen under hypoxic conditions. Here we summarize recent information on accumulation of HIF‐1α and p53 under hypoxia and provide a model to explain the communication between HIF‐1 and p53 under (patho)physiological conditions.

Keywords: HIF‐1, p53, hypoxia, apoptosis, transcription factor

References

  • 1. Nakayama K., Frew I.J., Hagensen, M. , Skals M., Habelhah H., Bhoumik A., Kadoya T., Erdjument‐Bromage H., Tempst P., Frappell P.B., Bowtell D.D., Ronai Z., Siah2 Regulates Stability of Prolyl‐Hydroxylases, Controls HIF1alpha Abundance, and Modulates Physiological Responses to Hypoxia, Cell, 117: 941–952, 2004. [DOI] [PubMed] [Google Scholar]
  • 2. Semenza G.L., Agani F., Booth G., Forsythe J., Iyer N., Jiang B.H., Leung S., Roe R., Wiener C., Yu A., Structural and functional analysis of hypoxia‐inducible factor 1, Kidney Int., 51: 553–555, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Wiesener M.S., Maxwell P.H., HIF and oxygen sensing; as important to life as the air we breathe?, Ann. Med., 35: 1830–190, 2003. [DOI] [PubMed] [Google Scholar]
  • 4. Zhu H., Jackson T., Bunn H.F., Detecting and responding to hypoxia, Nephrol. Dial. Transplant., 17: 3–7, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Kaelin W.G. Jr., How oxygen makes its presence felt, Genes Dev., 16: 1441–1445, 2002. [DOI] [PubMed] [Google Scholar]
  • 6. Metzen E., Ratcliffe P.J., HIF hydroxylation and cellular oxygen sensing, Biol Chem, 385: 223–230, 2004. [DOI] [PubMed] [Google Scholar]
  • 7. Poellinger L., Johnson R.S., HIF‐1 and hypoxic response: the plot thickens, Curr Opin Genet Dev, 14: 81–85, 2004. [DOI] [PubMed] [Google Scholar]
  • 8. Bracken C.P., Whitelaw M.L., Peet D.J., The hypoxiainducible factors: key transcriptional regulators of hypoxic responses, Cell Mol Life Sci, 60: 1376–1393, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Masson N., Ratcliffe P.J., HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O2 levels, J. Cell. Sci., 116: 3041–3049, 2003. [DOI] [PubMed] [Google Scholar]
  • 10. Semenza G.L., HIF‐1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus, Cell, 107: 1–3, 2001. [DOI] [PubMed] [Google Scholar]
  • 11. Lando D., Gorman J.J., Whitelaw M.L., Peet D.J., Oxygen‐dependent regulation of hypoxia‐inducible factors by prolyl and asparaginyl hydroxylation, Eur J Biochem, 270: 781–790, 2003. [DOI] [PubMed] [Google Scholar]
  • 12. Harris A.L., Hypoxia—a key regulatory factor in tumour growth, Nat Rev Cancer, 2: 38–47, 2002. [DOI] [PubMed] [Google Scholar]
  • 13. Lee J.W., Bae S.H., Jeong J.W., Kim S.H., Kim K.W., Hypoxia‐inducible factor (HIF‐1)alpha: its protein stability and biological functions, Exp Mol Med, 36: 1–12, 2004. [DOI] [PubMed] [Google Scholar]
  • 14. Semenza G.L., HIF‐1: mediator of physiological and pathophysiological responses to hypoxia, J Appl Physiol, 88: 1474–1480, 2000. [DOI] [PubMed] [Google Scholar]
  • 15. Semenza G.L., Expression of hypoxia‐inducible factor 1: mechanisms and consequences, Biochem Pharmacol, 59: 47–53, 2000. [DOI] [PubMed] [Google Scholar]
  • 16. Zhu H., Bunn H.F., Oxygen sensing and signaling: impact on the regulation of physiologically important genes, Respir Physiol, 115: 239–247, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Semenza G.L., Targeting HIF‐1 for cancer therapy, Nat Rev Cancer, 3: 721–732, 2003. [DOI] [PubMed] [Google Scholar]
  • 18. Li J., Zhang X., Sejas D.P., Bagby G.C., Pang Q., Hypoxia‐induced nucleophosmin protects cell death through inhibition of p53, J. Biol. Chem., 279: 41275–41279, 2004. [DOI] [PubMed] [Google Scholar]
  • 19. Goda, N. , Dozier, S.J. , and Johnson, R.S. , HIF‐1 in cell cycle regulation, apoptosis, and tumor progression, Antioxid Redox Signal, 5: 467–473, 2003. [DOI] [PubMed] [Google Scholar]
  • 20. Piret J.P., Mottet D., Raes M., Michiels C., Is HIF‐1α a pro‐ or an anti‐apoptotic protein?, Biochem. Pharmacol., 64: 889–892, 2002. [DOI] [PubMed] [Google Scholar]
  • 21. Acker T., Plate K.H., Hypoxia and hypoxia inducible factors (HIF) as important regulators of tumor physiology, Cancer Treat Res, 117: 219–248, 2004. [DOI] [PubMed] [Google Scholar]
  • 22. Bardos J.I., Ashcroft M., Hypoxia‐inducible factor‐1 and oncogenic signalling, Bioessays, 26: 262–269, 2004. [DOI] [PubMed] [Google Scholar]
  • 23. Melillo G., HIF‐1: a target for cancer, ischemia and inflammation—too good to be true?, Cell Cycle, 3: 154–155, 2004. [PubMed] [Google Scholar]
  • 24. Pugh C.W., Ratcliffe P.J., Regulation of angiogenesis by hypoxia: role of the HIF system, Nat. Med., 9: 677–684, 2003. [DOI] [PubMed] [Google Scholar]
  • 25. Choi K.S., Bae M.K., Jeong J.W., Moon H.E., Kim K.W., Hypoxia‐induced angiogenesis during carcinogenesis, J. Biochem. Mol. Biol., 36: 120–127, 2003. [DOI] [PubMed] [Google Scholar]
  • 26. Haupt Y., Robles A.I., Prives C., Rotter V., Deconstruction of p53 functions and regulation, Oncogene, 21: 8223–8231, 2002. [DOI] [PubMed] [Google Scholar]
  • 27. Vousden K.H., Activation of the p53 tumor suppressor protein, Biochim Biophys Acta, 1602: 47–59, 2002. [DOI] [PubMed] [Google Scholar]
  • 28. Oren M., Decision making by p53: life, death and cancer, Cell Death Differ, 10: 431–442, 2003. [DOI] [PubMed] [Google Scholar]
  • 29. Gottifredi V., Prives C., Molecular biology. Getting p53 out of the nucleus, Science, 292: 1851–1852, 2001. [DOI] [PubMed] [Google Scholar]
  • 30. Liang S.H., Clarke M.F., Regulation of p53 localization, Eur J Biochem, 268: 2779–2783, 2001. [DOI] [PubMed] [Google Scholar]
  • 31. Zhang Y., Xiong Y., A p53 amino‐terminal nuclear export signal inhibited by DNA damage‐induced phosphorylation, Science, 292: 1910–1915, 2001. [DOI] [PubMed] [Google Scholar]
  • 32. An W.G., Kanekal M., Simon M.C., Maltepe E., Blagosklonny M.V., Neckers L.M., Stabilization of wildtype p53 by hypoxia‐inducible factor 1α, Nature, 392: 405–408, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. Wenger R.H., Camenisch G., Desbaillets I., Chilov D., Gassmann M., Up‐regulation of hypoxia‐inducible factor‐1α is not sufficient for hypoxic/anoxic p53 induction, Cancer Res., 58: 5678–5680, 1998. [PubMed] [Google Scholar]
  • 34. Koumenis C., Alarcon R., Hammond E., Sutphin P., Hoffman W., Murphy M., Derr J., Taya Y., Lowe S.W., Kastan M., Giaccia A., Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53‐dependent transactivation, Mol. Cell. Biol., 21: 1297–1310, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Kaluzova M., Kaluz S., Lerman M.I., Stanbridge E.J., DNA damage is a prerequisite for p53‐mediated proteasomal degradation of HIF‐1 (alpha) in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX, Mol. Cell Biol., 24: 5757–5766, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Pan Y., Oprysko P.R., Asham A.M., Koch C.J., Simon M.C., p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment, Oncogene, 23: 4975–4983, 2004. [DOI] [PubMed] [Google Scholar]
  • 37. Halterman M.W., Miller C.C., Federoff H.J., Hypoxiainducible factor‐1α mediates hypoxia‐induced delayed neuronal death that involves p53, J. Neurosci., 19: 6818–6824, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Schmid T., Zhou J., Kohl R., Brune B., p300 relieves p53‐evoked transcriptional repression of hypoxiainducible factor‐1 (HIF‐1), Biochem J, 380: 289–295, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Hansson L.O., Friedler A., Freund S., Rudiger S., Fersht A.R., Two sequence motifs from HIF‐1α bind to the DNA‐binding site of p53, Proc. Natl. Acad. Sci. USA, 99: 10305–10309, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Chen D., Li M., Luo J., Gu W., Direct interactions between HIF‐1α and Mdm2 modulate p53 function, J. Biol. Chem., 278: 13595–13598, 2003. [DOI] [PubMed] [Google Scholar]
  • 41. Ravi R., Mookerjee B., Bhujwalla Z.M., Sutter C.H., Artemov D., Zeng Q., Dillehay L.E., Madan A., Semenza G.L., Bedi A., Regulation of tumor angiogenesis by p53‐induced degradation of hypoxia‐inducible factor 1α, Genes Dev., 14: 34–44, 2000. [PMC free article] [PubMed] [Google Scholar]
  • 42. Blagosklonny M.V., An W.G., Romanova L.Y., Trepel J., Fojo T., Neckers L., p53 inhibits hypoxia‐inducible factor‐stimulated transcription, J. Biol. Chem., 273: 11995–11998, 1998. [DOI] [PubMed] [Google Scholar]
  • 43. Datta K., Li J., Bhattacharya R., Gasparian L., Wang E., Mukhopadhyay D., Protein kinase C zeta transactivates hypoxia‐inducible factor alpha by promoting its association with p300 in renal cancer, Cancer Res., 64: 456–462, 2004. [DOI] [PubMed] [Google Scholar]

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