Abstract
Cyclin-dependent kinases (CDKs) play important roles in the control of fundamental cellular processes. Some of the most characterized CDKs are considered to be pertinent therapeutic targets for cancers and other diseases, and first clinical successes have recently been obtained with CDK inhibitors. Although discovered in the pre-genomic era, CDK10 attracted little attention until it was identified as a major determinant of resistance to endocrine therapy for breast cancer. In some studies, CDK10 has been shown to promote cell proliferation whereas other studies have revealed a tumor suppressor function. The recent discovery of Cyclin M as a CDK10 activating partner has allowed the unveiling of a protein kinase activity against the ETS2 oncoprotein, whose degradation is activated by CDK10/Cyclin M-mediated phosphorylation. CDK10/Cyclin M has also been shown to repress ciliogenesis and to maintain actin network architecture, through the phoshorylation of the PKN2 protein kinase and the control of RhoA stability. These findings shed light on the molecular mechanisms underlying STAR syndrome, a severe human developmental genetic disorder caused by mutations in the Cyclin M coding gene. They also pave the way to a better understanding of the role of CDK10/Cyclin M in cancer.
Highlights
Cyclin-dependent kinases (CDKs) form a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of a variety of fundamental cellular processes such as cell division, differentiation, migration and death through the control of transcription, splicing, and protein interactions, localization, stability, etc. [1, 2]
Discovered in the pre-genomic era, and at a time when the study of CDKs yielded major breakthroughs in the understanding of cell cycle regulation, CDK10 received little interest until it was identified as a major determinant of resistance to endocrine therapy for breast cancer [10]
CDK10 has been shown to be subject to ubiquitin-mediated degradation [27], and Cyclin M interaction may protect CDK10 from such degradation. These findings suggest that Cyclin M is the only conventional cyclin partner of CDK10 in MCF7 cells, in which an interaction between CDK10 and the unconventional Cyclin G2 has recently been reported [28]
Summary
Cyclin-dependent kinases (CDKs) form a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of a variety of fundamental cellular processes such as cell division, differentiation, migration and death through the control of transcription, splicing, and protein interactions, localization, stability, etc. [1, 2]. Co-expression of CDK10 and this chimera in human cells caused a significant inhibition of the transcription of a reporter gene. Silencing of either CDK10 or Cyclin M caused a strong increase in ETS2 protein expression levels, without affecting mRNA levels.
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