期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：32
页码：E3325-E3334
DOI：10.1073/pnas.1412840111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1 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 levels is unclear. Here we report that HIF-1 physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1 and increases HIF-1 protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1 at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1 is an essential step for the maintenance of cell-cycle progression under hypoxic conditions.
