The genetic basis of human keratinocyte immortalisation in squamous cell carcinoma development: the role of telomerase reactivation.
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.
Parkinson
E K
EK
Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow, U.K.
Newbold
R F
RF
Keith
W N
WN
D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004789:Enzyme Activation; D004793:Enzyme Reactivators; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*
D004793:Enzyme Reactivators; D019098:Telomerase