期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 42, 页码 30320-30329出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.507384
关键词
Apoptosis; Checkpoint Control; DNA Damage; p53; Tumor Suppressor Gene; Hippo Pathway; RASSF
资金
- Ministry of Education, Sports, Science, and Technology [17081008]
- Japan Society for the Promotion of Science (JSPS) [22790275, 22590267]
- Grants-in-Aid for Scientific Research [22790275, 17081008, 22590267] Funding Source: KAKEN
Ras association domain family (RASSF) 6 is a member of the C-terminal RASSF proteins such as RASSF1A and RASSF3. RASSF6 is involved in apoptosis in various cells under miscellaneous conditions, but it remains to be clarified how RASSF6 exerts tumor-suppressive roles. We reported previously that RASSF3 facilitates the degradation of MDM2, a major E3 ligase of p53, and stabilizes p53 to function as a tumor suppressor. In this study, we demonstrate that RASSF6 overexpression induces G(1)/S arrest in p53-positive cells. Its depletion prevents UV- and VP-16-induced apoptosis and G(1)/S arrest in HCT116 and U2OS cells. RASSF6-induced apoptosis partially depends on p53. RASSF6 binds MDM2 and facilitates its ubiquitination. RASSF6 depletion blocks the increase of p53 in response to UV exposure and up-regulation of p53 target genes. RASSF6 depletion delays DNA repair in UV- and VP-16-treated cells and increases polyploid cells after VP-16 treatment. These findings indicate that RASSF6 stabilizes p53, regulates apoptosis and the cell cycle, and functions as a tumor suppressor. Together with the previous reports regarding RASSF1A and RASSF3, the stabilization of p53 may be the common function of the C-terminal RASSF proteins.
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