期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 14, 页码 9662-9674出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.440552
关键词
-
资金
- National Institutes of Health [R01-GM090301, R01-CA153347]
Prolyl hydroxylase domain protein 2 (PHD2, also known as Egg Laying Defective Nine homolog 1) is a key oxygen-sensing protein in metazoans. In an oxygen-dependent manner, PHD2 site-specifically prolyl hydroxylates the master transcription factor of the hypoxic response, hypoxia-inducible factor-alpha (HIF-alpha), thereby targeting HIF-alpha for degradation. In this report we show that the heat shock protein 90 (HSP90) co-chaperones p23 and FKBP38 interact via a conserved Pro-Xaa-Leu-Glu motif (where Xaa = any amino acid) in these proteins with the N-terminal Myeloid Nervy and DEAF-1 (MYND)-type zinc finger of PHD2. Knockdown of p23 augments hypoxia-induced HIF-1 alpha protein levels and HIF target genes. We propose that p23 recruits PHD2 to the HSP90 machinery to facilitate HIF-1 alpha hydroxylation. These findings identify a link between two ancient pathways, the PHD: HIF and the HSP90 pathways, and suggest that this link was established concurrent with the emergence of the PHD: HIF pathway in evolution.
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