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• W2030228737 abstract "Mice harboring the p53 ‘m’ allele – the result of a 0.6-Mb deletion affecting the p53 N-terminus as well as its upstream region – alongside a normal copy of the p53 gene, show decreased lifespan, premature aging and reduced cancer incidence. In the June issue of Aging Cell , Gentry and Venkatachalam provide a characterization of the entire m region, identifying 23 genes located upstream of p53. These authors propose that at least part if not all of the phenotype associated with the presence of the ‘m’ allele is caused by haploinsufficiency of one or more of the deleted genes and not by a truncated p53. We disagree with their interpretation and believe that the truncated p53 protein is the major, and likely the sole contributor, to both early aging and low cancer incidence in this mouse mutant. Tyner et al . (2002) previously described mice with a shortened lifespan, early onset of a number of normal aging symptoms and low cancer incidence. These mice were mutated for p53 by conventional gene targeting in embryonic stem cells. However, the mutation was anything but conventional. Somehow a large region of DNA was deleted such that the N-terminus of p53 was removed along with an undetermined amount of DNA upstream of the p53 gene. The mutant allele was called the ‘m’ allele and is used in reference to p53. However, much more than p53 is affected by the ‘m’ allele. Homozygosity of this mutation results in embryonic lethality, so that the premature aging phenotype was only observed in heterozygotes, called p53 +/m . Tyner et al. suggested that accelerated aging in these mice is due to the expression of a truncated p53 protein. They found that mRNA specifically encoding the ‘m’ allele is expressed in almost all tissues of the p53 +/m mouse and translated into a p24 protein. However, the protein is hard to detect in vivo and it is unknown if other genes within the large deletion contribute to the aging phenotype. Thus, one could question if it is the truncated p53 protein that causes accelerated aging in the mouse or rather the haploinsufficiency of any or all of the genes residing in the genomic region affected by the deletion. In the June issue of Aging Cell , Gentry and Venkatachalam present their results that define the genetic alteration of the ‘m’ allele and show an approximate 0.6Mb deletion that contains at least 23 genes located upstream of p53 (Gentry & Venkatachalam, 2005). These authors propose that at least part if not all of the aging phenotype is caused by haploinsufficiency of one or more of the deleted genes and not by a truncated p53. We congratulate Gentry and Venkatachalam for characterizing the deleted region in the ‘m’ allele, which is important. However, we believe that their interpretation of the potential phenotypic consequences of the deletion confuse rather than clarify the issue of p53 as a putative pro-aging factor. We believe there are at least three problems with their interpretation in which they discount a truncated p53 as the culprit of the premature aging phenotype and the reduced cancer incidence in these mice. First, they fail to fully consider the ‘m’ allele in a genetic background deleted for wild-type p53 or adequately compare its effects with mice that overexpress full-length, normally regulated p53 or a natural variant of p53, i.e. p44. Second, they do not adequately compare the p53 +/m mice with other mutant mice that exhibit premature aging, possibly also involving p53 activity. Third, they do not provide direct evidence that haploinsufficiency of genes in the deleted region contribute to the premature aging phenotype. After all is considered, we believe that the truncated p53 protein is the major, and likely the sole contributor to both early aging and low cancer incidence, as we explain in more detail below." @default.
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• W2030228737 date "2005-12-01" @default.
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• W2030228737 title "Aging and p53: getting it straight A commentary on a recent paper by Gentry and Venkatachalam" @default.
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• W2030228737 doi "https://doi.org/10.1111/j.1474-9726.2005.00179.x" @default.
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