title: An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response.
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.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.forename: Laureano
authors.initials: L
authors.lastname: de la Vega
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D000098563:Seven in Absentia Proteins
chemical_list: D002352:Carrier Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex