Dual regulation of TERT activity through transcription and splicing by DeltaNP63alpha.
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.
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Esther
E
Vorovich
Edward A
EA
Ratovitski
D000107:Acetylation / Q000187:drug effects; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D017930:Genes, Reporter / Q000235:genetics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008957:Models, Genetic; D009284:Naphthols / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D007976:Leupeptins; D009284:Naphthols; D010750:Phosphoproteins; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; C439060:sirtinol; C077048:Hnrnpab protein, mouse; D012313:RNA; D004247:DNA; D019098:Telomerase; C509187:Tert protein, mouse; D001616:beta-Galactosidase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde