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  • Dual regulation of TERT activity through transcription and splicing by DeltaNP63alpha.

Dual regulation of TERT activity through transcription and splicing by DeltaNP63alpha.

Aging (2008-01-01)
Esther Vorovich, Edward A Ratovitski
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Sp1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
MG-132, InSolution, ≥98%, 10 mM, reversible proteasome inhibitor
Sigma-Aldrich
Anti-Sirt1(Sir2) Antibody, Upstate®, from rabbit
Sigma-Aldrich
Sirtinol, A cell-permeable 2-hydroxy-1-naphthaldehyde derivative that acts as a specific and direct inhibitor of the sirtuin class of deacetylase activity with no affect on human HDAC1.