| Autor: |
Ho Lin, Shuen-Chi You, Hsin-Yi Wang, Chia-Herng Yue, Eugene Lin, Yueh-Tsung Lee, Jo-Hsin Wang, Jer-Tsong Hsieh, Chih-Ho Lai, Yun-Chi Wang, Chih-Hsiang Chang, Wei-Hsiang Kao, Yu-Ting Peng, Mei-Chih Chen, Pao-Hsuan Huang |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6508415 |
| 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 |
| Externí odkaz: |
|
