期刊
CELL CYCLE
卷 10, 期 3, 页码 518-530出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.3.14756
关键词
CREG1; p16(INK4a); cellular immortalization; cellular senescence; Li-Fraumeni syndrome
类别
资金
- Barbara and Fred Erb Chair in Cancer Genetics
- Genomics and Flow Cytometry Core laboratories of the KCI CCSG [P30-CA022453]
- Royal Thai Government
Cellular senescence is an irreversible growth arrest that is activated in normal cells upon shortening of telomere and other cellular stresses. Bypassing cellular senescence is a necessary step for cells to become immortal during oncogenic transformation. During the spontaneous immortalization of Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes 1) expression was decreased during immortalization and increased in senescence. Moreover, we found that repression of CREG1 expression occurs via an epigenetic mechanism, promoter DNA methylation. Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines, cancers commonly seen in Li-Fraumeni Syndrome. In addition, we found that p16(INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16(INK4a), an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16(INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16(INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity, thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G(2)/M transition. In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16(INK4a)-induced senescence by transcriptional repression of cell cycle-regulated genes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据