Abstract
P53 homolog p63 was shown to play a role in premature ageing phenotype found in mouse models through regulation of the replicative senescence. We previously showed that the forced DeltaNp63alpha expression decreased the SIRT1 protein levels, and induced the replicative senescence of human keratinocytes, while the ectopic SIRT1 expression decreased the senescence. Using the DeltaNp63alpha overexpressing and p63-/+ heterozygous mice, we found that DeltaNp63alpha induced the mTERT promoter activation through the down regulation of the SIRT1 protein levels, inactivation of p53 deacetylation, decrease of the p53/Sp1 protein-protein interaction, and the overall induction of mTERT transcription regulation. In the same time, by a forming of protein-protein complexes with the ABBP1, DeltaNp63alpha induced the mTERT RNA splicing leading to an increasing expression of spliced mTERT isoforms playing a role of dominant-negative inhibitors of mTERT activity and therefore decreasing the levels of TERT activity in mouse epidermal keratinocytes. The overall effect of the DeltaNp63alpha overexpression resulted in decrease in telomerase activity and increase in replicative senescence observed in mouse keratinocytes. This dual molecular mechanism of telomerase regulation might underline the previously shown effect of DeltaNp63alpha on premature ageing phenotype.
Highlights
Cell senescence and stress modulate the proliferative potential of mammalian cells, suggesting that both are capable of suppressing the formation of tumors [1,2,3,4,5,6,7]
We investigated whether the above-mentioned treatments affect endogenous transcriptional regulation of mouse telomerase-reverse transcriptase (mTERT) promoter using the chromatin immunoprecipitation (ChIP) approach using an antibody against Sp1 as described elsewhere [53, 54]
Similar effect was found in cells transfected with Small hairpin RNA (shRNA) inhibiting SIRT1 or p53 expression, or in cells incubated with Sirtinol (100 μg/ml for 24 h). These results suggested that both SIRT1 and p53 functions play a critical role in transcription inhibition of the core mTERT promoter
Summary
Cell senescence and stress modulate the proliferative potential of mammalian cells, suggesting that both are capable of suppressing the formation of tumors [1,2,3,4,5,6,7]. Skin epidermis is one of the few regenerative tissues that express telomerase, the ribonucleoprotein complex that can counteract telomere erosion, one of the presently mostly favored potential mechanisms causing cellular ageing [18]. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might have a role in human disease [18,19,20,21,22,23,24]
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