Replicative senescence as a barrier to human cancer.
There is evidence that one critically short telomere may be recognized as DNA damage and, as a consequence, induce a p53/p21WAF- and p16INK4A-dependent G1 cell cycle checkpoint to cause senescence. Additionally, senescence via a p53- and p16(INK4A)-dependent mechanism can be induced by the over- or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the p14ARF protein, which connects oncogene activation, but not DNA damage, to p53 activation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but very often express a wild-type p14(ARF). Furthermore, when normal keratinocytes senesce they show a striking elevation of p16 protein, but not of p14(ARF) or its downstream targets p53 and p21(WAF). These results suggest that p16, rather than p14(ARF), is the more important gene in human keratinocyte senescence, but do not exclude a co-operative role for p14(ARF), perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.
Parkinson
E K
EK
The Beatson Institute for Cancer Research, CRC Beatson Laboratories, Glasgow, Scotland, UK.
Munro
J
J
Steeghs
K
K
Morrison
V
V
Ireland
H
H
Forsyth
N
N
Fitzsimmons
S
S
Bryce
S
S
D002352:Carrier Proteins / Q000235:genetics; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008957:Models, Genetic; D009369:Neoplasms / Q000517:prevention & control*; D011506:Proteins / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors