Vorovich Esther, Ratovitski Edward A
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Aging (Albany NY). 2008 Dec 9;1(1):58-67. doi: 10.18632/aging.100003.
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.
P53同源物p63已被证明通过调节复制性衰老，在小鼠模型中发现的早衰表型中发挥作用。我们之前表明，强制表达DeltaNp63alpha会降低SIRT1蛋白水平，并诱导人角质形成细胞的复制性衰老，而异位表达SIRT1则会减少衰老。使用过表达DeltaNp63alpha和p63基因杂合缺失（p63-/+）的小鼠，我们发现DeltaNp63alpha通过下调SIRT1蛋白水平、使p53去乙酰化失活、减少p53/Sp1蛋白-蛋白相互作用以及整体诱导mTERT转录调控来诱导mTERT启动子激活。同时，通过与ABBP1形成蛋白-蛋白复合物，DeltaNp63alpha诱导mTERT RNA剪接，导致剪接后的mTERT异构体表达增加，这些异构体发挥mTERT活性的显性负抑制剂作用，从而降低小鼠表皮角质形成细胞中的TERT活性水平。DeltaNp63alpha过表达的总体效果导致小鼠角质形成细胞中端粒酶活性降低和复制性衰老增加。这种端粒酶调节的双重分子机制可能是DeltaNp63alpha对早衰表型先前所示作用的基础。
