Parkinson E K, Newbold R F, Keith W N
Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow, U.K.
Eur J Cancer. 1997 Apr;33(5):727-34. doi: 10.1016/s0959-8049(97)00063-4.
Normal human keratinocytes have a finite replicative lifespan which culminates in senescence. Chromosomal telomere length may act as a mediator of replicative senescence, signalling cell cycle arrest in G1 when one or more telomeres become too short. Telomeric attrition in normal keratinocytes may be due to inadequate levels of telomerase activity and possibly also to oxidative damage. In advanced squamous cell carcinoma replicative senescence breaks down to yield immortal variants, in which several dominantly acting genes are functionally compromised, including p53 and the cyclin D-Cdk4/6 inhibitor CDKN2A/p16. The increased activity of both of these proteins would be expected to contribute to the G1 arrest in senescence and we have shown that levels of p16 are dramatically increased in senescent keratinocytes. In addition, two other genes which control a cell cycle G1 checkpoint independently of p53 and pRb appear dysfunctional. These genes are uncloned but map to chromosome 4q and 7q31.1 and appear to represent senescence complementation groups B and D, respectively. In immortal neoplastic keratinocytes, telomerase is strongly upregulated and there is evidence for a suppressor of the enzyme on the short arm of chromosome 3 mapping to 3p21.2-p21.3. We have also mapped the human telomerase RNA gene to 3q26.3 and found it to be overrepresented or amplified in a proportion of squamous cell tumours and cell lines. These observations may explain why isochromosome 3q is so common in human squamous carcinoma. None of these genetic alterations are seen in carcinomas which senesce and suggest that multiple genetic alterations are required for keratinocyte immortality.
正常人类角质形成细胞具有有限的复制寿命，最终会导致衰老。染色体端粒长度可能作为复制性衰老的调节因子，当一个或多个端粒变得过短时，在G1期发出细胞周期停滞的信号。正常角质形成细胞中的端粒磨损可能是由于端粒酶活性水平不足，也可能是由于氧化损伤。在晚期鳞状细胞癌中，复制性衰老会瓦解，产生永生变体，其中几个起主导作用的基因功能受损，包括p53和细胞周期蛋白D-Cdk4/6抑制剂CDKN2A/p16。预计这两种蛋白质活性的增加会导致衰老中的G1期停滞，并且我们已经表明p16水平在衰老的角质形成细胞中显著增加。此外，另外两个独立于p53和pRb控制细胞周期G1期检查点的基因似乎功能失调。这些基因尚未克隆，但分别定位于染色体4q和7q31.1，似乎分别代表衰老互补组B和D。在永生的肿瘤角质形成细胞中，端粒酶强烈上调，并且有证据表明在染色体3短臂上定位于3p21.2-p21.3的一种酶抑制因子。我们还将人类端粒酶RNA基因定位于3q26.3，并发现它在一部分鳞状细胞肿瘤和细胞系中过度表达或扩增。这些观察结果可能解释了为什么3号染色体等臂在人类鳞状细胞癌中如此常见。在衰老的癌中未观察到这些基因改变，这表明角质形成细胞永生需要多种基因改变。
