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

Lee, Ji-Won (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University)
Bae, Seong-Hui (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University)
Jeong, Joo-Won (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University)
Kim, Se-Hee (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University)
Kim, Kyu-Won (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University)
Publication Information
Experimental and Molecular Medicine / v.36, no.1, 2004 , pp. 1-12 More about this Journal
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 $HIF-1{\beta}$ subunit and one of three subunits $(HIF-1{\alpha},\;HIF-2{\alpha}\;or\;HIF-3{\alpha})$. The stability and activity of $HIF-1{\alpha}$ are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, $HIF-1{\alpha}$ interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the $HIF-1{\alpha}$ subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and $HIF-1{\alpha}$ 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, $HIF-1{\alpha}$ 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 $HIF-1{\alpha}$ is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of $HIF-1{\alpha}$ itself or $HIF-1{\alpha}$ 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 $HIF-1{\alpha}$ stability, the biological functions of HIF-1 and its potential applications of cancer therapies.
Keywords
ARD1; angiogenesis; anticancer therapy; cell proliferation/survival; HIF-1; glucose metabolismi; PHD; pVHL; p300/CBP; iron metabolism; transcription factor;
Citations & Related Records
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Times Cited By Web Of Science : 232  (Related Records In Web of Science)
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107 Identification of alternative spliced variants of human hypoxic-inducible factor-1alpha /
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108 The IGFBP-1 mRNA expression in HepG2 cells in affected by inhibition of heme biosynthesis /
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109 The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages /
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111 Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha /
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115 Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts /
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116 Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer /
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122 A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses /
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