Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth
| Autor: | Chih Hsiang Chang, Wei Hsiang Kao, Yun Chi Wang, Yueh Tsung Lee, Hsin Yi Wang, Eugene Lin, Mei Chih Chen, Yu Ting Peng, Chih Ho Lai, Jo Hsin Wang, Jer Tsong Hsieh, Shuen Chi You, Chia Herng Yue, Pao Hsuan Huang, Ho Lin |
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| Rok vydání: | 2016 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male 0301 basic medicine Cancer Research Mutant Mice Nude Biology Protein degradation Transfection Mice 03 medical and health sciences medicine Animals Humans Mice Inbred BALB C Cyclin-dependent kinase 5 Cyclin-dependent kinase 2 Cancer Cyclin-Dependent Kinase 5 medicine.disease Xenograft Model Antitumor Assays Molecular biology Cell biology 030104 developmental biology nervous system Oncology Cancer cell biology.protein Phosphorylation |
| Zdroj: | Cancer Research. 76:6888-6900 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-3253 |
| Popis: | 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 p21CIP1 from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21CIP1 through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21CIP1 protein degradation. S130A-p21CIP1 mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21CIP1 targeting 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. |
| Databáze: | OpenAIRE |
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