| First Author | Hubbi ME | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 32 | Pages | E3325-34 |
| PubMed ID | 25071185 | Mgi Jnum | J:213701 |
| Mgi Id | MGI:5585652 | Doi | 10.1073/pnas.1412840111 |
| Citation | Hubbi ME, et al. (2014) Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1alpha to promote cell-cycle progression. Proc Natl Acad Sci U S A 111(32):E3325-34 |
| abstractText | Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1alpha 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-1alpha levels is unclear. Here we report that HIF-1alpha physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1alpha and increases HIF-1alpha protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1alpha at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1alpha-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1alpha is an essential step for the maintenance of cell-cycle progression under hypoxic conditions. |
