Oncogenic Actions of SKP2 Involves Deregulation of CDK1 Turnover Mediated by FOXM1.
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.
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Anand
A
Krishnan
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Dhanya
D
K
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Saneesh
S
Babu P S
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Sankar
S
Jagadeeshan
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Manu
M
Prasad
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
S Asha
SA
Nair
D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007972:Leukoplakia, Oral / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D023081:CCAAT-Binding Factor; C093090:CKS1B protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C492061:NFYA protein, human; D015513:Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
CELL CYCLE; FoxM1; cdk1; cks1; skp2