An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response.
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.
Calzado
Marco A
MA
Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.
de la Vega
Laureano
L
Möller
Andreas
A
Bowtell
David D L
DD
Schmitz
M Lienhard
ML
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
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