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首页> 外文期刊>Cell cycle >CREG1 enhances p16(INK4a) -induced cellular senescence.
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CREG1 enhances p16(INK4a) -induced cellular senescence.

机译：CREG1增强p16（INK4a）诱导的细胞衰老。

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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.
机译：细胞衰老是不可逆的生长停滞，其在端粒缩短和其他细胞应激缩短后在正常细胞中被激活。绕过细胞衰老是细胞在致癌转化过程中永生的必不可少的步骤。在Li-Fraumeni综合征（LFS）成纤维细胞自发永生化过程中，我们发现CREG1（E1A刺激的基因1的细胞阻遏物）表达在永生化过程中降低，并在衰老中增加。此外，我们发现抑制CREG1表达的发生是通过表观遗传机制，即启动子DNA甲基化。永生LFS细胞系中CREG1的异位表达可降低细胞增殖，但不直接诱导衰老。我们在骨肉瘤和纤维肉瘤癌细胞系（Li-Fraumeni综合征中常见的癌症）中证实了这一点。此外，我们发现p16（INK4a）在永生细胞中也被下调，CREG1和p16（INK4a）（CDK4 / 6和Rb磷酸化的抑制剂）的共表达比单独的CREG1和p16（INK4a）具有更大的作用。减少永生的LFS成纤维细胞，骨肉瘤和纤维肉瘤细胞系中的细胞生长，诱导细胞周期停滞和细胞衰老。此外，CREG1和p16（INK4a）的协同作用通过抑制启动子活性从而降低mRNA和蛋白质水平来抑制细胞周期蛋白A和细胞周期蛋白B的表达。这些蛋白质是S期进入和G2 / M过渡所必需的。总之，这是第一个证明CREG1通过转录抑制细胞周期调控基因增强p16（INK4a）诱导的衰老的证据。

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