Tumor suppression and normal aging in mice with constitutively high p53 activity

Mendrysa, Susan M.; O’Leary, Kathleen A.; McElwee, Matthew K.; Michalowski, Jennifer; Eisenman, Robert N.; Powell, Douglas; Perry, Mary Ellen

doi:10.1101/gad.1378506

Cited by 195 publications

(194 citation statements)

References 27 publications

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“…They are many reports that support this notion. Firstly, haploinsufficiency effects were observed in cells from the p53 þ /À mice and the opposite effect was observed from mice carrying the hypomorphic mdm2 allele (Harvey et al, 1993;Mendrysa et al, 2003Mendrysa et al, , 2006. Cells from these mice were shown to have reduced or elevated p53 levels, which consistently affected proliferation and apoptotic rates accordingly.…”

Section: Discussionmentioning

confidence: 99%

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

Phang

Sabapathy

2006

Oncogene

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Human p53, unlike mouse p53, contains a polymorphic site at codon 72 in exon 4 encoding either an arginine amino acid (72R) or a proline residue (72P). The 72R form was shown to induce apoptosis better than the 72P form, partly owing to its ability to efficiently bind to the nuclear-export protein CRM1 and localize to the mitochondria. This polymorphism has also been associated with cancer predisposition and chemo-sensitivity. Further understanding of the in vivo significance of this polymorphism in carcinogenesis requires the generation of mouse models. We have thus evaluated if the polymorphism-specific effects of human p53 are retained in mouse cells. Though being transcriptionally active, both the human polymorphs were found to have lost their ability to differentially suppress growth and bind to CRM1 or MDM2 in mouse cells. Moreover, chimaeric proteins containing mouse exons 2-3 and human exons 4-11 have also lost the polymorphism-specific effects in human cells, suggesting that human exons 2-3 are important in regulating the polymorphism-specific effects. Furthermore, human p53 and the various chimaeric proteins were generally less effective in inhibiting growth of mouse cells compared to mouse p53, suggesting that mouse p53 is more potent than human p53 in suppressing growth, partly due to enhanced binding of MDM2 to human p53. The data together suggest that mouse cells may not provide an appropriate environment for the manifestation of the polymorphism-specific functional differences of human p53, and hence, cautions against the expression of fulllength or chimaeric p53 proteins in mice to study the effects of the polymorphism.

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Section: Discussionmentioning

confidence: 99%

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

Phang

Sabapathy

2006

Oncogene

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“…Mice with 30% of total Mdm2 levels had decreased incidence of tumors in the small intestine in an APC min/ þ background. 43 Additionally, a single nucleotide polymorphism identified in the human mdm2 promoter that increases slightly the levels of Mdm2 is associated with an increased age of tumor onset in Li-Fraumeni syndrome patients already compromised for p53 levels. 44 These data indicate that small changes in Mdm2 may have some longterm consequences and function as a modifier of a tumor phenotype.…”

Section: Minor Changes In Mdm2 and Mdm4 Levels Reveal Important Phenomentioning

confidence: 99%

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

et al. 2006

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“…Importantly, not all models of altered p53 activity exhibit accelerated aging (Table 1). In some cases, increased p53 can result in cancer resistance without apparent effects on longevity (Garcia-Cao et al, 2002;Mendrysa et al, 2006). On the other hand, in two mouse models of extended longevity, p53 activities are shown to be abrogated (Table 1, p66 Shc and Klotho TG).…”

Section: How Does the Dna Damage Response Suppress Igf-1 Signaling?mentioning

confidence: 99%

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

Hinkal

Donehower

2008

Mechanisms of Ageing and Development

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Long-lived animals have evolved a robust set of defenses to maintain genomic integrity over their entire lifespan. The DNA damage response and DNA repair pathways are critical pillars of organismal defenses, minimizing somatic mutations in both post-mitotic and mitotic cells. These genomic maintenance systems not only prevent the premature emergence of cancers, but may also maintain normal tissue function and organismal longevity. Genetic defects in a number of DNA repair and DNA damage response genes often leads to a dramatic increase in cancer incidence; in other cases, premature aging or progeroid syndromes may be induced. In this review, we discuss two recent reports of two nucleotide excision repair deficient models that exhibit dramatic premature aging and shortened longevity. The DNA repair defects were also associated with a significant inhibition of the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis, an endocrine signaling pathway shown to influence aging and longevity in both vertebrates and invertebrates. Potential mechanisms of how DNA damage might affect IGF-1 signaling and aging are discussed, with a particular emphasis on the role of such signaling alterations in the adult tissue stem cell compartments.

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Tumor suppression and normal aging in mice with constitutively high p53 activity

Cited by 195 publications

References 27 publications

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

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