Complex regulation of CDK2 and G1 arrest during neuronal differentiation of human prostatic cancer TSU-Prl cells by staurosporine.
We are interested in the possibility of new prostate cancer therapy that would control tumor malignancy via the induction of terminal cell differentiation. We have previously reported that staurosporine induced remarkable inhibition of cell proliferation and neuronal differentiation in human prostatic cancer TSU-Pr1 cells. In the present study, we investigated the alteration of cyclin-dependent kinase (CDK) activities and cell cycle in differentiated TSU-Pr1 cells. Treatment of TSU-Pr1 cells with staurosporine resulted in G1 arrest and suppression of CDK2 activity. Protein levels of CDK2 were essentially unchanged during this time. p21 protein, however, rapidly increased for 6 hours after treatment with staurosporine. p27 protein also increased gradually for 12 to 72 hours after treatment. CDK2-bound p21 and CDK2-bound p27 also increased. These results suggest that an increase in p21 and p27 protein causes increased binding with CDK2 and inhibition of CDK2 activity. We propose that the complex regulation of CDK2 plays a key role in G1 arrest of TSU-Pr1 cells after treatment with staurosporine.
Shimizu
T
T
Department of Hygiene-Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya Funagawara-Machi, Shinjuku-ku, Tokyo 162-0826, Japan.
Takahashi
N
N
Tachibana
K
K
Takeda
K
K
D042846:CDC2-CDC28 Kinases; D002454:Cell Differentiation / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000378:metabolism; D009124:Muscle Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D019311:Staurosporine / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000096:biosynthesis; D020764:cdc42 GTP-Binding Protein / Q000096:biosynthesis / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D019925:Cyclin A; D019927:Cyclin E; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D020764:cdc42 GTP-Binding Protein; D019311:Staurosporine; D000095043:Cyclin-Dependent Kinase-Activating Kinase