p53 mutant mice that display early ageing-associated phenotypes

Tyner, Stuart D.; Venkatachalam, Sundaresan; Choi, Jeongyong; Jones, Stephen N.; Ghebranious, Nader; Igelmann, Herbert; Lu, Xiongbin; Soron, Gabrielle; Cooper, Benjamin; Brayton, Cory; Park, Sang Hee; Thompson, Timothy; Karsenty, Gérard; Bradley, Allan; Donehower, Lawrence A.

doi:10.1038/415045a

Cited by 1,357 publications

(1,092 citation statements)

References 35 publications

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“…Exceptions to the above are the p53/p44 and the AT‐1 sTg systems. In the case of p53/p44, the primary defect is in the N‐terminal regulatory functions of the p53 protein, which leads to reduced stemness potential of stem cells as well as hyperactivation of IGF‐1R signaling (Campisi, 2004; Lessel et al, 2017; Maier et al, 2004; Pehar, Ko, Li, Scrable, & Puglielli, 2014; Tyner et al, 2002). AT‐1 sTg mice display many features that are in line with classical segmental progerias, such as reduced growth, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Discussionmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…Another major finding of the current investigation was that the RGS14 KO mice showed an extension in lifespan in both males and females and did not exhibit many of the adverse effects of aging normally observed in mice, such as decreased thymus weight, body atrophy, or loss of body hair (Gui, Mustachio, Su & Craig, 2012; Tyner et al., 2002). The current field of aging‐related research is focused more on extending a healthful lifespan, rather than simply extending lifespan, as older individuals with complications of aging that impair the quality of life often do not feel that further extension of lifespan is desirable.…”

Section: Discussionmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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“…Knockin homozygote mice (p53 DNp53/DNp53 ), expressing only amino-truncated p53 proteins, are cancer-prone like p53 À/À mice, and do not show any accelerated aging phenotype, indicating that that is dependent on the effect in trans of DNp53 on wild-type p53. 67,68 Knockin heterozygote p53 mice (p53 þ /M ) expressing one mutant p53 allele, bearing a point mutation in the DNA binding domain, are as susceptible to cancer as heterozygote p53 þ /À mice but do not show any accelerated aging phenotype. 69,70 This indicates that DNp53 proteins and point mutant p53, mutated in the DNA-binding domain, act…”

Section: Biological Activities Of P53 and Its Isoformsmentioning

confidence: 99%

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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Abstractp63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation. Cell Death and Differentiation (2006) Introduction p53 was discovered in 1979 as a protein interacting with the oncogenic T antigen from SV40 virus. 1-5 p53 protein is the product of a pivotal tumor-suppressor gene whose inactivation by mutation or interaction with viral or overexpressed cellular proteins occurs in almost all cancers. 6 The p53 protein integrates multiple cellular stress signals assessing cellular damages to trigger either cell-cycle arrest or programmed cell death (apoptosis). 7 These effects are predominantly due to p53's ability to bind DNA through p53-responsive element (p53RE) 8,9 and regulate the transcription of genes involved in these processes, such as p21 10 (cell cycle arrest), Puma 11 or Scotin 12 (apoptosis). Thereby, p53 prevents proliferation of genetically abnormal cells and thus cancer formation.Two p53-related genes, p63 and p73, were identified in 1997. 13,14 The high level of sequence similarity between p63, p73 and p53 proteins, particularly in the DNA binding domain, allows p63 and p73 to transactivate p53-responsive genes causing cell cycle arrest and apoptosis. Therefore, p63, p73 and p53 genes form a family of transcription factor. However, they are not functionally entirely redundant and the primary role of each p53 family member -as determined by transgenetic knockout mice -illustrates that each protein has its own unique functions.We recently published that the p53 gene family has a dual gene structure conserved from drosophila to man. 15 Like most of the genes in the human genome, 16 p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. Hence, p53 gene family members express different forms of p53 protein containing different domain of the protein (isoforms). In this review, we will summarise the different isoforms of p63, p73 and p53 expressed in human, mouse and drosophila. p63The mouse p63 gene is composed of 15 exons spanning over 208 000 bp (GenBank Accession Number: AF533892) on chromosome 16, while the human p63 gene is composed of 15 exons, spanning over 270 000 bp on chromosome 3q2...

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p53 mutant mice that display early ageing-associated phenotypes

Cited by 1,357 publications

References 35 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

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