a critical role for fbxw8 and mapk in cyclin d1 degradation and cancer cell proliferation关键角色fbxw8和mapk在细胞周期蛋白d1退化和癌症细胞增殖.pdfVIP

A Critical Role for FBXW8 and MAPK in Cyclin D1 Degradation and Cancer Cell Proliferation Hiroshi Okabe1,3, Sang-Hyun Lee2,3, Janyaporn Phuchareon1,3, Donna G. Albertson2,3, Frank McCormick2,3, Osamu Tetsu1,3* 1 Department of Pathology, School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 2 Cancer Research Institute, School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 3 UCSF Comprehensive Cancer Center, School of Medicine, University of California San Francisco, San Francisco, California, United States of America Cyclin D1 regulates G1 progression. Its transcriptional regulation is well understood. However, the mechanism underlying cyclin D1 ubiquitination and its subsequent degradation is not yet clear. We report that cyclin D1 undergoes increased degradation in the cytoplasm during S phase in a variety of cancer cells. This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase. The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase. In contrast, cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm in S phase. Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm, and enhanced phosphorylation of cyclin D1 through sustained ERK1/2 signaling. Depletion of FBXW8 caused a significant accumulation of cyclin D1, as well as sequestration of CDK1 in the cytoplasm. This resulted in a severe reduction of cell proliferation. These effects could be rescued by constitutive nuclear expression of cyclin D1-T286A. Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present