PT  - JOURNAL ARTICLE
AU  - Kyung-Ok Choi
AU  - Taekyong Lee
AU  - Naery Lee
AU  - Ji-Hyun Kim
AU  - Eun Gyeong Yang
AU  - Jung Min Yoon
AU  - Jin Hwan Kim
AU  - Tae Gyu Lee
AU  - Hyunsung Park
TI  - Inhibition of the Catalytic Activity of Hypoxia-Inducible Factor-1α-Prolyl-Hydroxylase 2 by a MYND-Type Zinc Finger
AID  - 10.1124/mol.105.015271
DP  - 2005 Dec 01
TA  - Molecular Pharmacology
PG  - 1803--1809
VI  - 68
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/68/6/1803.short
4100  - http://molpharm.aspetjournals.org/content/68/6/1803.full
SO  - Mol Pharmacol2005 Dec 01; 68
AB  - Hypoxia-induced gene expression is initiated when the hypoxia-inducible factor-1 (HIF-1) α subunit is stabilized in response to a lack of oxygen. An HIF-1α-specific prolyl-hydroxylase (PHD) catalyzes hydroxylation of the proline-564 and/or -402 residues of HIF-1α 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-1α. 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-1α than did overexpression of wild-type PHD2, indicating that the MYND domain also inhibits the catalytic activity of PHD2 in vivo.