Kwon Nam Hoon, Lee Jin Young, Ryu Ye-Lim, Kim Chanhee, Kong Jiwon, Oh Seongeun, Kang Beom Sik, Ahn Hye Won, Ahn Sung Gwe, Jeong Joon, Kim Hoi Kyoung, Kim Jong Hyun, Han Dae Young, Park Min Chul, Kim Doyeun, Takase Ryuichi, Masuda Isao, Hou Ya-Ming, Jang Sung Ill, Chang Yoon Soo, Lee Dong Ki, Kim Youngeun, Wang Ming-Wei, Kim Sunghoon
Medicinal Bioconvergence Research Center, Seoul National University, Suwon, 16229, Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Korea.
ACS Pharmacol Transl Sci. 2018 Apr 24;1(1):21-31. doi: 10.1021/acsptsci.8b00001. eCollection 2018 Sep 14.
Although abnormal increases in the level or activity of cyclin-dependent kinase 4 (CDK4) occur frequently in cancer, the underlying mechanism is not fully understood. Here, we show that methionyl-tRNA synthetase (MRS) specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MRS reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MRS on CDK4 stability were more prominent in the tumor suppressor p16-negative cancer cells because of the competitive relationship of the two proteins for binding to CDK4. Suppression of MRS reduced cell transformation and the tumorigenic ability of a p16-negative breast cancer cell line . Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.
尽管细胞周期蛋白依赖性激酶4（CDK4）的水平或活性异常增加在癌症中频繁发生，但其潜在机制尚未完全了解。在此，我们表明甲硫氨酰-tRNA合成酶（MRS）通过增强CDK4与伴侣蛋白之间复合物的形成来特异性稳定CDK4。敲低MRS会降低CDK4水平，导致G0/G1细胞周期停滞。由于这两种蛋白在与CDK4结合上存在竞争关系，MRS对CDK4稳定性的影响在肿瘤抑制因子p16阴性癌细胞中更为显著。抑制MRS会降低p16阴性乳腺癌细胞系的细胞转化和致瘤能力。此外，在p16阴性人乳腺癌组织中，MRS水平与CDK4水平及下游信号高频呈正相关。这项工作揭示了这两种涉及蛋白质合成和细胞周期的酶之间意想不到的功能联系。
