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

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1 alpha 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-1 alpha levels is unclear. Here we report that HIF-1 alpha physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1 alpha and increases HIF-1 alpha protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1 alpha at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1 alpha-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1 alpha is an essential step for the maintenance of cell-cycle progression under hypoxic conditions.