Choi, KO Lee, T Lee, N Kim, JH Yang, EG Yoon, JM Kim, JH Lee, TG Park, H 2024-01-21T04:05:42Z 2024-01-21T04:05:42Z 2021-09-02 2005-12 0026-895X https://pubs.kist.re.kr/handle/201004/135971 Hypoxia-induced gene expression is initiated when the hypoxiainducible factor-1 (HIF-1) alpha subunit is stabilized in response to a lack of oxygen. An HIF-1 alpha-specific prolyl-hydroxylase (PHD) catalyzes hydroxylation of the proline-564 and/or -402 residues of HIF-1 alpha by an oxygen molecule. The hydroxyproline then interacts with the ubiquitin E3 ligase von Hippel Lindau protein and is degraded by an ubiquitin-dependent proteasome. PHD2 is the most active of three PHD isoforms in hydroxylating HIF-1 alpha. Structural analysis showed that the N-terminal region of PHD2 contains a Myeloid translocation protein 8, Nervy, and DEAF1 (MYND)-type zinc finger domain, whereas the catalytic domain is located in its C-terminal region. We found that deletion of the MYND domain increased the activity of both recombinant PHD2 protein and in vitro-translated PHD2. The zinc chelator N, N, N', N'-tetrakis(2-pyridylmethyl) ethylenediamine augmented the activity of wild-type PHD2-F but not that of PHD2 lacking the MYND domain, confirming that the zinc finger domain is inhibitory. Overexpression of PHD2 lacking the MYND domain caused a greater reduction in the stability and function of HIF-1 alpha than did overexpression of wild-type PHD2, indicating that the MYND domain also inhibits the catalytic activity of PHD2 in vivo. English AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS UBIQUITIN-PROTEASOME PATHWAY PROLYL HYDROXYLATION FACTOR 1-ALPHA HIF PROLYL PROTEIN TRANSCRIPTION FAMILY DOMAIN ALPHA GENE Inhibition of the catalytic activity of hypoxia-inducible factor-1 alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger Article 10.1124/mol.105.015271 1 MOLECULAR PHARMACOLOGY, v.68, no.6, pp.1803 - 1809 MOLECULAR PHARMACOLOGY 68 6 1803 1809 scie scopus 000233340200031 2-s2.0-27844605466 Pharmacology & Pharmacy Pharmacology & Pharmacy Article UBIQUITIN-PROTEASOME PATHWAY PROLYL HYDROXYLATION FACTOR 1-ALPHA HIF PROLYL PROTEIN TRANSCRIPTION FAMILY DOMAIN ALPHA GENE