Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Cell Cycle. 2011 Feb 1;10(3):518-30. doi: 10.4161/cc.10.3.14756.
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 G2/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.
细胞衰老（Cellular senescence）是一种不可逆的生长停滞，当端粒缩短和其他细胞应激时，正常细胞会激活这种生长停滞。绕过细胞衰老（Cellular senescence）是细胞在致癌转化过程中变得不朽所必需的步骤。在 Li-Fraumeni 综合征（Li-Fraumeni Syndrome，LFS）成纤维细胞的自发永生化过程中，我们发现 CREGl（细胞 E1A 刺激基因的抑制因子 1）的表达在永生化过程中降低，而在衰老过程中增加。此外，我们发现 CREGl 表达的抑制是通过表观遗传机制，即启动子 DNA 甲基化发生的。在永生化的 LFS 细胞系中异位表达 CREGl 可降低细胞增殖，但不能直接诱导衰老。我们在骨肉瘤和纤维肉瘤癌细胞系中证实了这一点，这些癌症在 Li-Fraumeni 综合征中很常见。此外，我们发现 p16（INK4a）在永生化细胞中也下调，CREGl 和 p16（INK4a）的共表达，即 CDK4/6 和 Rb 磷酸化的抑制剂，比 CREGl 和 p16（INK4a）单独表达更能有效地降低细胞生长、诱导细胞周期停滞和 LFS 永生化成纤维细胞、骨肉瘤和纤维肉瘤细胞系中的细胞衰老。此外，CREGl 和 p16（INK4a）的合作通过抑制启动子活性抑制细胞周期调节基因的表达，从而降低细胞周期蛋白 A 和 B 的 mRNA 和蛋白水平；这些蛋白是 S 期进入和 G2/M 期过渡所必需的。总之，这是第一个证明 CREGl 通过转录抑制细胞周期调节基因增强 p16（INK4a）诱导的衰老的证据。
