title: Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth.
abstract: The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21CIP1from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21CIP1through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21CIP1protein degradation. S130A-p21CIP1mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21CIP1targeting primarily appears in S-phase, while Cdk5 overexpression increases the activation of Cdk2 and its interaction with DNA polymerase δ. The in vivo results show that Cdk2 might play an important role in the downstream signaling to Cdk5. In summary, these findings suggest that Cdk5 in a high expression status promotes cancer growth by directly and rapidly releasing p21CIP1-dependent cell-cycle inhibition and subsequent Cdk2 activation, which illustrates an oncogenic role of Cdk5 potentially applied for future diagnosis and therapy. Cancer Res; 76(23); 6888-900. ©2016 AACR.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Pao-Hsuan
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Mei-Chih
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Peng
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Kao
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Yun-Chi
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jo-Hsin
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.|Department of Surgery, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Yueh-Tsung
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.|Department of Urology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Eugene
authors.initials: E
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.|Department of Surgery, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan.
authors.forename: Chia-Herng
authors.initials: CH
authors.lastname: Yue
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.|Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shuen-Chi
authors.initials: SC
authors.lastname: You
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan. hlin@dragon.nchu.edu.tw.|Department of Biotechnology, Asia University, Taichung, Taiwan.|Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human