p12(CDK2-AP1) mediates DNA damage responses induced by cisplatin.
We examined the biological role of p12(CDK2-AP1) in cisplatin-mediated responses by using murine ES p12(CDK2-AP1) knockout clones generated by a targeted disruption of murine p12(CDK2-AP1). Homozygous knockout clones showed an increased cellular proliferation along with an increase in S and a decrease in G2/M phase populations. Interestingly, ES p12(CDK2-AP1) knockout clones showed a resistance to cisplatin treatment along with an increased DNA repair activity assessed by host cell reactivation assay using a cisplatin-damaged reporter DNA and a significant reduction of apoptosis upon cisplatin treatment. By using stable p12(CDK2-AP1) short interfering RNA (siRNA) clones from human normal oral keratinocytes, we confirmed that downregulation of p12(CDK2-AP1) resulted in a resistance to cisplatin. More interestingly, cisplatin treatment resulted in a reduction of CDK2 kinase activity in control clones, but p12(CDK2-AP1) knockout clones showed a sustained CDK2 kinase activity. These data suggest that p12(CDK2-AP1) plays a role in cisplatin-mediated cellular responses by modulating CDK2 activity. These data further suggest p12(CDK2-AP1) is a potential gene therapeutic agent for oral/head and neck cancer in conjunction with DNA-damaging agents such as cisplatin.
Kim
Yong
Y
School of Dentistry and Dental Research Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
McBride
Jim
J
Zhang
Rong
R
Zhou
Xiaofeng
X
Wong
David T
DT
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000235:genetics*; D017931:DNA Primers; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms; D051379:Mice; D009062:Mouth Neoplasms; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013234:Stem Cells; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
D000970:Antineoplastic Agents; D017931:DNA Primers; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C496849:Cdk2ap1 protein, mouse; D002945:Cisplatin