Normal @entity1 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 @entity957 replicative senescence breaks down to yield immortal variants, in which several dominantly acting genes are functionally compromised, including @entity876 and the cyclin D- @entity20405 inhibitor @entity986 / @entity986 . 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 @entity986 are dramatically increased in senescent keratinocytes. In addition, two other genes which control a cell cycle G1 checkpoint independently of @entity876 and @entity996 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- @entity994 .3. We have also mapped the @entity1 telomerase RNA gene to 3q26.3 and found it to be overrepresented or amplified in a proportion of @entity5 and cell lines. These observations may explain why isochromosome 3q is so common in @entity1 @entity957 . None of these genetic alterations are seen in @entity189 which senesce and suggest that multiple genetic alterations are required for keratinocyte immortality.

The genetic basis of XXXX keratinocyte immortalisation in @entity957 development: the role of telomerase reactivation.

@entity1 :: ('9606', 'Species') :: ['human'] @entity20405 :: ('1019;1021', 'Gene') :: ['Cdk4/6'] @entity986 :: ('1029', 'Gene') :: ['CDKN2A', 'p16'] @entity5 :: ('MESH:D009369', 'Disease') :: ['squamous cell tumours'] @entity996 :: ('5925', 'Gene') :: ['pRb'] @entity957 :: ('MESH:D002294', 'Disease') :: ['advanced squamous cell carcinoma', 'squamous carcinoma'] @entity189 :: ('MESH:D002277', 'Disease') :: ['carcinomas'] @entity876 :: ('7157', 'Gene') :: ['p53'] @entity994 :: ('1026', 'Gene') :: ['p21']
@entity1 :: (9606,Species) :: ['human']
