Gil Jesús, Bernard David, Martínez Dolores, Beach David
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
Nat Cell Biol. 2004 Jan;6(1):67-72. doi: 10.1038/ncb1077. Epub 2003 Nov 30.
In contrast to cancer cells and embryonic stem cells, the lifespan of primary human cells is finite. After a defined number of population doublings, cells enter in an irreversible growth-arrested state termed replicative senescence. Mutations of genes involved in immortalization can contribute to cancer. In a genetic screen for cDNAs bypassing replicative senescence of normal human prostate epithelial cells (HPrEC), we identified CBX7, a gene that encodes a Polycomb protein, as shown by sequence homology, its interaction with Ring1 and its localization to nuclear Polycomb bodies. CBX7 extends the lifespan of a wide range of normal human cells and immortalizes mouse fibroblasts by downregulating expression of the Ink4a/Arf locus. CBX7 does not inter-function or colocalize with Bmi1, and both can exert their actions independently of each other as shown by reverse genetics. CBX7 expression is downregulated during replicative senescence and its ablation by short-hairpin RNA (shRNA) treatment inhibited growth of normal cells though induction of the Ink4a/Arf locus. Taken together, these data show that CBX7 controls cellular lifespan through regulation of both the p16(Ink4a)/Rb and the Arf/p53 pathways.
与癌细胞和胚胎干细胞不同，原代人类细胞的寿命是有限的。在经历一定数量的群体倍增后，细胞进入一种不可逆的生长停滞状态，即复制性衰老。参与永生化的基因突变可能导致癌症。在一项针对绕过正常人前列腺上皮细胞（HPrEC）复制性衰老的cDNA的遗传筛选中，我们鉴定出CBX7，它是一个编码多梳蛋白的基因，这可通过序列同源性、其与Ring1的相互作用以及其在核多梳体中的定位得以证明。CBX7可延长多种正常人细胞的寿命，并通过下调Ink4a/Arf基因座的表达使小鼠成纤维细胞永生化。CBX7不与Bmi1相互作用或共定位，反向遗传学研究表明二者均可独立发挥作用。CBX7的表达在复制性衰老过程中下调，通过短发夹RNA（shRNA）处理将其敲除可通过诱导Ink4a/Arf基因座抑制正常细胞的生长。综上所述，这些数据表明CBX7通过调节p16(Ink4a)/Rb和Arf/p53两条途径来控制细胞寿命。
