Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-beta: but p53 mutations are not necessarily required.
Our previous work showed that acquisition of immortality at the dysplasia stage of oral cancer progression was consistently associated with four changes: loss of retinoic acid receptor (RAR)-beta and p16INK4A expression, p53 mutations and activation of telomerase. One atypical dysplasia (D17) that underwent delayed senescence after an extended lifespan showed loss of RAR-beta and p16INK4A/p14ARF expression, but retained functional wild-type p53 and telomerase was not activated. We now demonstrate that retroviral delivery of hTERT results in telomere lengthening and immortalization of D17 without loss of functional wild-type p53 activity. In contrast, the expression of hTERT in two other typical mortal dyplasia cultures (that retain RAR-beta and p16INK4A expression) does not extend their lifespan, even though telomeres are lengthened.
The Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Alessandra
A
Muntoni
Janis
J
Fleming
Katrina E
KE
Gordon
Keith
K
Hunter
Fiona
F
McGregor
E Kenneth
EK
Parkinson
Paul R
PR
Harrison
D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004268:DNA-Binding Proteins; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009061:Mouth Mucosa / Q000473:pathology*; D009062:Mouth Neoplasms / Q000473:pathology*; D009154:Mutation; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D016615:Telomere
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019098:Telomerase