REVIEW

The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

A E Greijer¹, E van der Wall²

¹ Departments of Pathology and Medical Oncology, VU University Medical Centre, Amsterdam, 1081 HV, The Netherlands
² Departments of Pathology and Medical Oncology, UMCU, Utrecht, 3508 GA, The Netherlands

Correspondence to:
Correspondence to:
Dr A E Greijer
Departments of Pathology and Medical Oncology, VU University Medical Centre, Amsterdam, 1081 HV, The Netherlands; ae.greijer{at}vumc.nl

Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxia induced apoptosis occurs. These resistant tumours probably have a more aggressive phenotype and may have decreased responsiveness to treatment. The key regulator of this process, hypoxia inducible factor 1 (HIF-1), can initiate apoptosis by inducing high concentrations of proapoptotic proteins, such as BNIP3, and can cause stabilisation of p53. However, during hypoxia, antiapoptotic proteins, such as IAP-2, can be induced, whereas the proapoptotic protein Bax can be downregulated. During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. Understanding the regulation of apoptosis during hypoxia and the mechanisms of resistance to apoptosis might lead to more specific treatments for solid tumours.

Abbreviations: Apaf-1, apoptotic protease activating factor-1; BNIP3, BCL-2/adenovirus E1B 19 kDa interacting protein 3; ES, embryonic stem; HIF-1, hypoxia inducible factor 1; HRE, hypoxia response element; IAP-2, inhibitor of apoptosis protein2; IRES, internal ribosome entry site; Jab1, jun activation domain binding protein 1; JNK, c-Jun NH₂ terminal kinase; NF-B, nuclear factor B; ODD, oxygen dependent degradation; PI3K, phosphoinositide-3 kinase; ROS, reactive oxygen species; SAPK, stress activated protein kinase; VHL, von Hippel Lindau

Keywords: hypoxia; apoptosis; hypoxia inducible factor 1; tumour

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HIF-1 and cellular fate

Richard G Fiddian-Green

JCP Online, 12 Jan 2006 [Full text]