Oncogenic Actions of SKP2 Involves Deregulation of CDK1 Turnover Mediated by FOXM1.

Abstract

Cyclin-dependent kinases (cdks) are central catalytic units of cell division cycle. Among the cdk family members, cdk1 has critical roles in multiple phases of the cell cycle. Aberrant expression or hyper-actions of cdk1 are tumorigenic and yet the complex oncogenic network that regulates its turnover is poorly understood. We found a hitherto unexplored functional connection between skp2 and cdk1 turn over. In vitro knockdown or overexpression of skp2 in cultured cells reduced or induced cdk1 expression indicating skp2 as a positive driver for cdk1. A partial inhibitory role for p27 was identified in this context. Interestingly, concurrent overexpression of skp2 and p27 favored cdk1 upregulation in vitro, which correlated well with similar observations in clinical tumor samples. We found that the transcription factor FOXM1 may play a central role in the skp2-cdk1 loop. Additional molecular involvement in the skp2-cdk1 loop was also explored. In conclusion, our results revealed hitherto unexplored p27 independent molecular mechanisms for skp2 driven tumor progression. Our results support the previous findings that skp2 may be a potential therapeutic target for the management of tumors. J. Cell. Biochem. 118: 797-807, 2017. © 2016 Wiley Periodicals, Inc.