CREG1 enhances p16INK4a-induced cellular senescence
CREG1 enhances p16INK4a-induced cellular senescence
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DOI：
10.4161/cc.10.3.14756
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发表时间：
2011-02-01
期刊：
影响因子：
4.3
通讯作者：
Tainsky, Michael A.
中科院分区：
文献类型：
--
作者：
Moolmuang, Benchamart;Tainsky, Michael A.
细胞衰老是一种不可逆的生长停滞，在端粒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过程中不朽的必要步骤。在Li-Fraumeni综合征（LFS）成纤维细胞的自发永生中，我们发现CREG1（E1A刺激的基因的细胞抑制剂1）在永生化期间表达降低，并在衰老中增加。此外，我们发现CREG1表达的抑制是通过表观遗传机理，启动子DNA甲基化发生的。不朽的LFS细胞系中CREG1的异位表达会降低细胞的增殖，但不会直接诱导衰老。我们在骨肉瘤和纤维肉瘤癌细胞系中证实了这一点，这是Li-fraumeni综合征中常见的癌症。此外，我们发现p16（ink4a）在不朽的细胞中也被下调，并且CREG1和P16的共表达（Ink4a）是CDK4/6和RB磷酸化的抑制剂，其作用比CREG1和P16（INK4A）具有更大的作用。为了减少细胞生长，诱导不朽的LFS成纤维细胞中的细胞周期停滞和细胞衰老，骨肉瘤和纤维肉瘤细胞系。此外，CREG1和P16（INK4A）的合作通过抑制启动子活性来抑制细胞周期蛋白A和细胞周期蛋白B的表达，从而降低mRNA和蛋白质水平。这些蛋白质是S期进入和G（2）/M跃迁所必需的。总之，这是第一个证明CREG1通过转录抑制细胞周期调节基因来增强p16（Ink4a）诱导的衰老的证据。
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.