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

ABSTRACT: 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.

SUBMITTER: Hubbi ME

PROVIDER: S-EPMC4136593 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Hubbi Maimon E ME Gilkes Daniele M DM Hu Hongxia H Kshitiz Ahmed Ishrat I Semenza Gregg L GL

Proceedings of the National Academy of Sciences of the United States of America 20140728 32

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 ...[more]

PMID: 25071185

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Project description:IntroductionCell cycle-associated cyclin-dependent kinases (ccCDKs) are essential regulators known to control cell division and facilitate tumorigenesis and progression. However, there is currently no comprehensive study of distinct ccCDKs in prostate cancer (PCa). The purpose of this study was to determine the value of ccCDK expression in predicting the prognosis of patients with PCa and to identify the gene functions of ccCDK in PCa.MethodsThe UALCAN databases were analyzed to examine the expression of CDKs in prostate cancer. The Human Protein Atlas was used to verify the expression of CDKs online. Then, we assessed the prognostic values of CDKs using GEPIA. GeneMANIA and Metascape analyses were used to predict biological functions. We analyzed the mutation of CDKs by cBioPortal. The TIMER database was used to evaluate the correlation of CDKs and immune infiltration. The expression of CDKs in tissue was examined through quantitative real-time polymerase chain reaction. After that, we focused on CDK3 and identified the expression of CDK3 by immunohistochemistry and western blot. The functions of CDK3 in C4-2 cell proliferation were determined by CCK-8 assays. C4-2 cells were tested for their ability to invade and migrate through transwell and wound healing assays.ResultsThe results showed that CDK1/3/4/5/6/16 was expressed at relatively higher levels in PCa tissues than in normal tissues. Patients with low expression of CDK1/3/5/16 exhibited significantly better disease-free survival than those with high expression. ccCDKs were enriched in the IL-18 signaling pathway and correlated with the infiltration of immune cells in PCa. Moreover, our cohort study data verified that there were significantly higher expression of CDK1/3/5/16 in PCa tissues compared to benign prostate hyperplasia tissues, and CDK3 was remarkably associated with a shorter progression-free survival for biochemical recurrence in PCa patients. CDK3 was positively expressed in PCa cells and tissues, and functional experiments demonstrated that silencing CDK3 inhibited PCa cell proliferation, migration, and invasion.ConclusionsOur study provides new evidence of ccCDKS in promoting PCa progression and implies that CDK3 may serve as an oncogene in PCa and may be valuable in the prognosis of biochemical recurrence in PCa patients.

Dataset Information

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

Publications

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

Similar Datasets

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