TY - JOUR
T1 - Trim45 functions as a tumor suppressor in the brain via its e3 ligase activity by stabilizing p53 through k63-linked ubiquitination
AU - Zhang, Jindong
AU - Zhang, Chuanxia
AU - Cui, Jun
AU - Ou, Jiayu
AU - Han, Jing
AU - Qin, Yunfei
AU - Zhi, Feng
AU - Wang, Rong Fu
N1 - Funding Information:
Acknowledgements. This work was supported by National Natural Science Foundation of China (91629101 and 31522018), National Key Basic Research Program of China (2015CB859800, 2014CB910800 and 2014CB745203), Guangdong Natural Science Funds for Distinguished Young Scholar (S2013050014772), Guangdong Innovative Research Team Program (Nos 2011Y035 and 201001Y0104687244), the Fundamental Research Funds for the Central Universities (15lgjc02), and the Training Program for Outstanding Young Teachers in Higher Education institutions of Guangdong Province (YQ2015001). R-FW was, in part, supported by grants (CA101795 and DA030338) from NCI and NIDA, NIH. FZ is partially supported by the National Natural Science Foundation of China (81302197), Jiangsu Provincial Special Programe of Medical Science (BL2014035), Changzhou Science and Technology Support Program (CE20165048), Changzhou High-Level Medical Talents Training Project (2016CZBJ006), and Changzhou Municipal Commisions of Health and Family Planning Major Scientific and Technological Project (ZD201620).
Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - Tripartite motif-containing protein 45 (TRIM45) belongs to a large family of RING-finger-containing E3 ligases, which are highly expressed in the brain. However, little is known regarding the role of TRIM45 in cancer biology, especially in human glioma. Here, we report that TRIM45 expression is significantly reduced in glioma tissue samples. Overexpression of TRIM45 suppresses proliferation and tumorigenicity in glioblastoma cells in vitro and in vivo. In addition, CRISPR/Cas9-mediated knockout of TRIM45 promotes proliferation and inhibits apoptosis in glioblastoma cells. Further mechanistic analyses show that TRIM45 interacts with and stabilizes p53. TRIM45 conjugates K63-linked polyubiquitin chain to the C-terminal six lysine residues of p53, thereby inhibiting the availability of these residues to the K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 is a novel tumor suppressor that stabilizes and activates p53 in glioma.
AB - Tripartite motif-containing protein 45 (TRIM45) belongs to a large family of RING-finger-containing E3 ligases, which are highly expressed in the brain. However, little is known regarding the role of TRIM45 in cancer biology, especially in human glioma. Here, we report that TRIM45 expression is significantly reduced in glioma tissue samples. Overexpression of TRIM45 suppresses proliferation and tumorigenicity in glioblastoma cells in vitro and in vivo. In addition, CRISPR/Cas9-mediated knockout of TRIM45 promotes proliferation and inhibits apoptosis in glioblastoma cells. Further mechanistic analyses show that TRIM45 interacts with and stabilizes p53. TRIM45 conjugates K63-linked polyubiquitin chain to the C-terminal six lysine residues of p53, thereby inhibiting the availability of these residues to the K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 is a novel tumor suppressor that stabilizes and activates p53 in glioma.
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U2 - 10.1038/cddis.2017.149
DO - 10.1038/cddis.2017.149
M3 - Article
C2 - 28542145
AN - SCOPUS:85032837729
SN - 2041-4889
VL - 8
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - e2831
ER -