Gao Gui-Bin, Sun Yue, Fang Run-Dong, Wang Ying, Wang Yang, He Qing-Yu
MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China.
Mol Biomed. 2021 Jul 20;2(1):22. doi: 10.1186/s43556-021-00029-0.
Post-translational modifications (PTMs) of Cyclin-dependent kinase 5 (CDK5) have emerged as important regulatory mechanisms that modulate cancer development in patients. Though CDK5 is an atypical member of the cyclin-dependent kinase family, its aberrant expression links to cell proliferation, DNA damage response, apoptosis, migration and angiogenesis in cancer. Current studies suggested that, new PTMs on CDK5, including S-nitrosylation, sumoylation, and acetylation, serve as molecular switches to control the kinase activity of CDK5 in the cell. However, a majority of these modifications and their biological significance in cancer remain uncharacterized. In this review, we discussed the role of PTMs on CDK5-mediated signaling cascade, and their possible mechanisms of action in malignant tumors, as well as the challenges and future perspectives in this field. On the basis of the newly identified regulatory signaling pathways of CDK5 related to PTMs, researchers have investigated the cancer therapeutic potential of chemical compounds, small-molecule inhibitors, and competitive peptides by targeting CDK5 and its PTMs. Results of these preclinical studies demonstrated that targeting PTMs of CDK5 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted.
细胞周期蛋白依赖性激酶5（CDK5）的翻译后修饰（PTM）已成为调节癌症患者癌症发展的重要调控机制。尽管CDK5是细胞周期蛋白依赖性激酶家族的非典型成员，但其异常表达与癌症中的细胞增殖、DNA损伤反应、细胞凋亡、迁移和血管生成有关。目前的研究表明，CDK5上的新翻译后修饰，包括S-亚硝基化、SUMO化和乙酰化，作为分子开关来控制细胞中CDK5的激酶活性。然而，这些修饰中的大多数及其在癌症中的生物学意义仍未得到表征。在本综述中，我们讨论了翻译后修饰在CDK5介导的信号级联反应中的作用，以及它们在恶性肿瘤中的可能作用机制，以及该领域的挑战和未来前景。基于新发现的与翻译后修饰相关的CDK5调控信号通路，研究人员通过靶向CDK5及其翻译后修饰，研究了化合物、小分子抑制剂和竞争性肽的癌症治疗潜力。这些临床前研究的结果表明，靶向CDK5的翻译后修饰产生了有前景的抗肿瘤作用，并且这些治疗策略的临床转化是有必要的。
