HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation

Lavinia Nardinocchi, Rosa Puca, Gabriella D'Orazi

Research output: Contribution to journalArticle

Abstract

Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF-1α subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1α and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1α protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1α upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1α by siRNA, HIF-1α-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1α and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies.

Original languageEnglish
Pages (from-to)33-43
Number of pages11
JournalAging
Volume3
Issue number1
Publication statusPublished - Jan 2011

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Keywords

  • HIF-1α
  • HIPK2
  • p53 transcriptional activity
  • p53Ser46
  • Proteasomal degradation
  • Zinc

ASJC Scopus subject areas

  • Ageing
  • Cell Biology
  • Geriatrics and Gerontology

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