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Nat Cell Biol. 2009 Jan;11(1):85-91. doi: 10.1038/ncb1816. Epub 2008 Nov 30.

An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response.

Author information

1
Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.

Abstract

Oxygen deprivation (hypoxia) results in reprogrammed gene expression patterns that induce multifaceted cellular responses. Here we identify a regulated interaction between the serine/threonine kinase HIPK2 and the ubiquitin E3 ligase Siah2 as a mechanism controlling the hypoxic response. Under normoxic conditions, several mechanisms ensure HIPK2 stability: only a fraction of HIPK2 is found in association with Siah2, whereas HIPK2-mediated phosphorylation of this E3 ligase at positions 26, 28 and 68 weakens mutual binding and destabilizes its phosphorylated interaction partner. Hypoxic conditions allow a markedly increased HIPK2/Siah2 interaction and result in efficient polyubiquitylation and proteasomal degradation of the kinase. Accordingly, hypoxia-induced HIPK2 elimination is markedly reduced in Siah2-deficient cells. As HIPK2 has an important role as a negative regulator of gene expression, its elimination from promoter-associated repressor complexes allows the induction of a substantial fraction of hypoxia-induced genes.

PMID:
19043406
DOI:
10.1038/ncb1816
[Indexed for MEDLINE]

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