Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Maimon E. Hubbi, Daniele M. Gilkes, Hongxia Hu, K. Kshitiz, Ishrat Ahmed, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)E3325-E3334
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number32
DOIs
StatePublished - Aug 12 2014

Keywords

  • Cell proliferation
  • Chaperone mediated autophagy
  • Lysosome

ASJC Scopus subject areas

  • General

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