S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Theses (Master's Degree_분자의학 및 바이오제약학과)
An Oncogenic Variant of AIMP2 Enhances K-Ras Stability via Heat Shock Protein Complex
발암성 변이체 AIMP2가 Heat Shock Protein Complex을 매개체로 하여 K-Ras를 안정화시켜 대장암을 유발시키는 과정에 대한 규명
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 서울대학교 대학원
- AIMP2-DX2; Colorectal Cancer; Hsp70; Hsp90; Heat Shock Protein Complex; K-Ras; Oncogenicity; Pathological implication; Therapeutic implication
- 학위논문 (석사)-- 서울대학교 대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2018. 2. 김성훈.
- K-Ras is one of Ras small GTPase family and it facilitates diverse cell signaling. Many researches have shown that mutated K-Ras induces colorectal cancer. For last few decades, there have been intensive efforts to understand oncological implications of mutated K-Ras and to control its stability. However, these efforts fail to provide the amplification mechanisms of pathological level of K-Ras and also they could not provide clinically useful outcome to control the activity or expression level of K-Ras.
Here, I report the veiled mechanism of the pathological implication and stabilization of K-Ras. I propose AIMP2-DX2, as known as an exon2-deleted splicing variant of AIMP2 (aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2), is the key factor regulating K-Ras. The GST domain of AIMP2-DX2 binds to the hypervariable region of K-Ras specifically. After AIMP2-DX2 and K-Ras interact each other, AIMP2-DX2 recruits the heat shock proteins, HSP70 and HSP90, to facilitated proper folding of K-Ras. This process enhances the stability and oncogenicity of K-Ras, which results the aggressive tumor progression. In the presence of both proteins, AIMP2-DX2 and K-Ras, the tumor progression is much more noticeable in vitro, in vivo conditions and tissue samples of colorectal cancer patients.
Therefore, I suggest that regulating the level of AIMP2-DX2 could be the one of the key factors to control the stability and oncogenicity of K-Ras. Through this study, I believe that AIMP2-DX2-mediated novel mechanism of K-Ras is a strong therapeutic implication of colorectal cancer.