Letter abstract
Nature Cell Biology 11, 85 - 91 (2008)
Published online: 30 November 2008 | doi:10.1038/ncb1816
An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response
Marco A. Calzado1, Laureano de la Vega1, Andreas Möller2,3, David D. L. Bowtell2,3 & M. Lienhard Schmitz1
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.
- Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.
- Peter MacCallum Cancer Centre, Department of Research, Cancer Genomics and Biochemistry Laboratory, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
- University of Melbourne, Department of Biochemistry and Molecular Biology, Parkville, Victoria 3010, Australia.
Correspondence to: M. Lienhard Schmitz1 e-mail: lienhard.schmitz@biochemie.med.uni-giessen.de
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Targeting tumors through the HIF systemNature Medicine News and Views (01 Dec 2000)
Fresh air is good for nerves: hypoxia disturbs axon guidanceNature Neuroscience News and Views (01 Aug 2008)
See all 3 matches for News And ViewsRESEARCH
Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor proteinThe EMBO Journal Article (15 Aug 2000)
Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATRNature Cell Biology Article (01 Jul 2008)
See all 67 matches for Research
