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Journal of Biochemistry Advance Access published online on October 28, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp167
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

JB Review

Cellular signal transduction of the hypoxia response

Koh Nakayama*

Medical Top Track program Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

*To whom correspondence should be addressed: Koh Nakayama 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan 113-8510 Phone/Fax: +81-3-5803-4815 Email: nakayama.mtt{at}mri.tmd.ac.jp

Received September 11, 2009; Accepted October 6, 2009


  Abstract

Cells induce the hypoxia responses to adapt to the environment when organisms are exposed to a low oxygen environment. The hypoxia response leads to the activation of multiple cellular signaling pathways involved in regulation of respiration, metabolism, cell survival and so forth. Hypoxia-Inducible-Factor (HIF) pathway plays a central role during the hypoxia response as its expression and activity are regulated in an oxygen-dependent manner and it also regulates the expression of multiple hypoxia responsive genes. The expression of HIF is regulated by proline hydroxylation, which is mediated by HIF prolyl-hydroxylase named PHD. The hydroxylated HIF-alpha subunit is degraded via the ubiquitin-proteasome pathway. The PHD activity needs to be strictly regulated to ensure the stabilization of HIF under hypoxic conditions, because PHD leads to HIF degradation. This review describes the regulatory mechanism of HIF stability and activity under normoxia and hypoxic conditions. Furthermore, the role of the HIF-independent pathways during the hypoxia response, which is as important as the HIF pathway, will also be described.

Key Words: HIF, PHD, prolyl-hydroxylation, Siah2, ubiquitination


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