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Cellular oxygen sensing: Molecular ...

Chan, Denise A.

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Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability./
作者:	Chan, Denise A.
面頁冊數:	127 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1682.
Contained By:	Dissertation Abstracts International65-04B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128361
ISBN:	0496756230

Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability.
Chan, Denise A.

Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability. - 127 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1682.

Thesis (Ph.D.)--Stanford University, 2004.

Hypoxia-inducible factor-1 is essential for the cellular response to low oxygen conditions. HIF-1 is a heterodimeric transcription factor, composed of an oxygen-labile alpha subunit and a constitutive beta subunit. HIF-1 drives the transcription of many genes involved in variety of cellular processes, including oxygen homeostasis, glycolysis, angiogenesis, and differentiation. The principal method of regulation is through the oxygen sensitivity of the alpha subunit. Under normal oxygenated conditions, HIF-1alpha is hydroxylated by a family of prolyl hydroxylases on two highly conserved proline residues, proline 402 and proline 564. These post-translational modifications allow the E3 ubiquitin ligase VHL to interact. Binding of VHL to HIF-1alpha results in proteasomal degradation of HIF-1alpha. As the hydroxylation reaction absolutely requires oxygen as a cofactor, the activity of the prolyl hydroxylases is abrogated by hypoxia, or low oxygen tensions. Thus, VHL does not interact and HIF-1alpha is stabilized. Stabilized HIF-1alpha is able to dimerize with HIF-1beta to drive gene transcription of target genes.

ISBN: 0496756230Subjects--Topical Terms:

1017719
Biology, Molecular.

Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability.
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245 1 0 $a Cellular oxygen sensing: Molecular characterization of hypoxia-inducible factor-1 alpha protein stability.
300 $a 127 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1682.
500 $a Adviser: Amato J. Giaccia.
502 $a Thesis (Ph.D.)--Stanford University, 2004.
520 $a Hypoxia-inducible factor-1 is essential for the cellular response to low oxygen conditions. HIF-1 is a heterodimeric transcription factor, composed of an oxygen-labile alpha subunit and a constitutive beta subunit. HIF-1 drives the transcription of many genes involved in variety of cellular processes, including oxygen homeostasis, glycolysis, angiogenesis, and differentiation. The principal method of regulation is through the oxygen sensitivity of the alpha subunit. Under normal oxygenated conditions, HIF-1alpha is hydroxylated by a family of prolyl hydroxylases on two highly conserved proline residues, proline 402 and proline 564. These post-translational modifications allow the E3 ubiquitin ligase VHL to interact. Binding of VHL to HIF-1alpha results in proteasomal degradation of HIF-1alpha. As the hydroxylation reaction absolutely requires oxygen as a cofactor, the activity of the prolyl hydroxylases is abrogated by hypoxia, or low oxygen tensions. Thus, VHL does not interact and HIF-1alpha is stabilized. Stabilized HIF-1alpha is able to dimerize with HIF-1beta to drive gene transcription of target genes.
520 $a We have created two novel hydroxy-specific antibodies to examine the molecular regulation of HIF-1alpha by these prolyl hydroxylations. With these antibodies we have been able to directly examine these modifications in response to different HIF-1alpha stabilizing stresses in the context of the full-length protein in vivo. We investigated whether the oncogenic stimulation of HIF-1 a protein under normoxic conditions involves the prolyl hydroxylases, identifying a differential mechanism regulating hydroxylation, depending on the type of oncogenic stress. Our data suggests that v-Src and Ras affect the stabilization of HIF-1alpha under normoxia through the inhibition of the prolyl hydroxylase enzymes. Constitutive Akt, on the other hand, induced HIF-1alpha protein in normoxia, but this induction was downstream of the prolyl hydroxylases. Furthermore, we have been able to examine how the two sites interact, if at all, and the relative contribution of the two sites in protein stabilization. Additional experiments aim to examine the life cycle of HIF-1alpha protein. Furthermore, these reagents are easily transferred to other researchers. Collaborative experiments utilizing these antibodies are described.
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790 1 0 $a Giaccia, Amato J., $e advisor
790 $a 0212
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128361