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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cell Hypoxia / genetics
  • Cell Line
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Macromolecular Substances / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics

Substances

  • Carrier Proteins
  • Macromolecular Substances
  • Nuclear Proteins
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex