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

M.A. Calzado, L. de la Vega, A. Möller, D.D.L. Bowtell, M.L. Schmitz (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    90 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)85-91
    Number of pages7
    JournalNature Cell Biology
    Volume11
    Issue number1
    DOIs
    Publication statusPublished - Jan 2009

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