Stabilization of Cyclin-Dependent Kinase 4 by Methionyl-tRNA Synthetase in p16INK4a-Negative Cancer.

Abstract

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 p16INK4a-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 p16INK4a-negative breast cancer cell line in vivo. Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16INK4a-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.

• Authors: Nam Hoon Kwon, Jin Young Lee, Ye-Lim Ryu, Chanhee Kim, Jiwon Kong, Seongeun Oh, Beom Sik Kang, Hye Won Ahn, Sung Gwe Ahn, Joon Jeong, Hoi Kyoung Kim, Jong Hyun Kim, Dae Young Han, Min Chul Park, Doyeun Kim, Ryuichi Takase, Isao Masuda, Ya-Ming Hou, Sung Ill Jang, Yoon Soo Chang, Dong Ki Lee, Youngeun Kim, Ming-Wei Wang, Basappa, Sunghoon Kim
• Journal: ACS pharmacology & translational science (ACS Pharmacol Transl Sci) Vol. 1 Issue 1 Pg. 21-31 (Sep 14 2018) ISSN: 2575-9108 [Electronic] United States
• PMID: 32219202 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 American Chemical Society.