Exp Mol Med.  2004 Feb;36(1):1-12.

Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions

• Lee JW
• Bae SH
• Jeong JW
• Kim SH
• Kim KW

Abstract

Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and its potential applications of cancer therapies.

Keyword

ARD1; angiogenesis; anticancer therapy; cell proliferation/survival; HIF-1; glucose metabolismi; PHD; pVHL; p300/CBP; iron metabolism; transcription factor

MeSH Terms

Alternative Splicing
Gene Expression Regulation
Gene Therapy
Growth Substances/metabolism
Humans
Protein Isoforms/chemistry/genetics/*metabolism
Protein Subunits/genetics/metabolism
Research Support, Non-U.S. Gov't
Signal Transduction/physiology
Transcription Factors/chemistry/genetics/*metabolism
Transcription, Genetic