An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response
- 30 November 2008
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 11 (1), 85-91
- https://doi.org/10.1038/ncb1816
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.This publication has 25 references indexed in Scilit:
- Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATRNature, 2008
- Ubiquitination and Degradation of Homeodomain-interacting Protein Kinase 2 by WD40 Repeat/SOCS Box Protein WSB-1Online Journal of Public Health Informatics, 2008
- MDM2-Regulated Degradation of HIPK2 Prevents p53Ser46 Phosphorylation and DNA Damage-Induced ApoptosisMolecular Cell, 2007
- Phosphorylation-Dependent Control of Pc2 SUMO E3 Ligase Activity by Its Substrate Protein HIPK2Molecular Cell, 2006
- Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2The EMBO Journal, 2006
- Coupling phosphoryl transfer and substrate interactions in protein kinasesBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2005
- Siah2 Regulates Stability of Prolyl-Hydroxylases, Controls HIF1α Abundance, and Modulates Physiological Responses to HypoxiaCell, 2004
- Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLKJournal of Bone and Joint Surgery, 2004
- Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2Nature, 2001
- Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosisNature, 2001