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.
Muntoni
Alessandra
A
The Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Fleming
Janis
J
Gordon
Katrina E
KE
Hunter
Keith
K
McGregor
Fiona
F
Parkinson
E Kenneth
EK
Harrison
Paul R
PR
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