S-Space College of Pharmacy (약학대학) Dept. of Manufacturing Pharmacy (제약학과) Theses (Master's Degree_제약학과)
Methionyl-tRNA synthetase modulates proliferation of triple-negative breast cancer via controlling CDK4 stability
- 약학대학 제약학과
- Issue Date
- 서울대학교 대학원
- MRS (Methionyl-tRNA synthetase); CDK4 (cyclin-dependent kinase 4); TNBC (Triple Negative Breast Cancer); cell proliferation
- 학위논문 (석사)-- 서울대학교 대학원 : 제약학과, 2014. 2. 김성훈.
- Aminoacyl-tRNA synthetases (ARSs), charging amino acid to the cognate tRNA, mediate various signal pathways in response to growth, stress and apoptotic stimuli. Among them, Methionyl-tRNA synthetase (MRS) is known to relocate from cytosol to nucleus under growth condition, however the meaning and function of MRS in the nucleus is not clearly understood.
We found that knockdown of MRS triggered growth retardation of triple negative breast cancer (TNBC) cells. G1/S transition of cell cycles was impaired by MRS knockdown based on the flow cytometry analysis suggesting that MRS may be involved in the cell cycle control. We, therefore investigated the relationship between MRS and cell cycle regulation-related proteins and observed that level of cyclin-dependent kinase 4 (CDK4) was critically affected by MRS expression level. MRS specifically interact with CDK4 based on the pull-down assay and immunoprecipitation assay. Hsp90-cdc37-CDK4 complex, which controls the stability of CDK4 was co-immunoprecipitated with MRS, and knockdown of MRS significantly reduced the level of CDK4 resulting in cell growth arrest under growth condition. MRS knockdown-mediated cell growth retardation was recovered by overexpression of CDK4 suggesting that maintenance of CDK4 stability via interaction with MRS is critical for cell proliferation. Stable knockdown of MRS significantly influenced on the anchorage-independent colony formation of TNBC cell line. This study suggests the novel function of MRS on the regulation of cell proliferation via controlling CDK4 stability and possible role of MRS as a promising therapeutic target for TNBC treatment.