Does p53 affect organismal aging?

Donehower, Lawrence A.

doi:10.1002/jcp.10104

Cited by 141 publications

(72 citation statements)

References 151 publications

(174 reference statements)

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“…Senescence in cultured cells is associated with an increased p53 activity and abrogation of p53 activity may delay in vitro senescence. 16,17,34,35 Such abnormally activated p53 signaling pathway has been observed also in Zmpste24 -/-mice. 17 By generating Zmpste24 -/-p53 -/-mice, it has been demonstrated that the premature aging phenotype exhibited by the Zmpste24 -/-null mice was partially recovered, thus demonstrating that the absence of p53 rescues some molecular alterations observed in Zmpste24 -/-mice.…”

Section: Discussionmentioning

confidence: 76%

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Masi¹,

D’Apice²,

Ricordy³

et al. 2008

Cell Cycle

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Mandibuloacral dysplasia type A (MADA; OMIM # 248370) is a premature ageing disease caused by the homozygous R527H mutation in the LMNA gene. At the cellular level, MADA is characterized by unprocessed prelamin A accumulation, nuclear architecture alterations, chromatin defects and increased incidence of apoptosis. In some progeroid laminopathies (e.g., HGPS) it has been demonstrated that such biochemical and morphological alterations are strongly linked with genomic instability. To test this also in MADA fibroblasts, their response to the ionising radiationinduced damage was analysed. We observed that their ability to repair the damage was significantly impaired, as demonstrated by the increased chromosome damage and the higher percentage of residual γ-H2AX foci, corresponding to unrepaired DNA-damage sites. Moreover, MADA fibroblasts showed a markedly reduced phosphorylation of p53 at Ser15(S15) and a lower induction of p53 and CDKN1A proteins after irradiation, compared to the control cell line. Upon irradiation, we also detected differences in the expression of some p53 downstream target genes. In addition, MADA cells showed partial defects in the checkpoint response, particularly in G 1 /S transition.Our results indicate that accumulation of the lamin A precursor protein determines a defect in DNA damage response after X-ray exposure, supporting a crucial role of lamin A in regulating DNA repair process and cell cycle control.

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Section: Discussionmentioning

confidence: 76%

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Masi¹,

D’Apice²,

Ricordy³

et al. 2008

Cell Cycle

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“…The role of p53 as a tumor suppressor is well established: nearly 80% of human cancers display defects in p53 signalling, while half of all cancers harbor structural alterations in the p53 gene. 20,37 On the other hand, in senescent cells-characterized by their inability to proliferate-although the levels of p53 protein are not elevated, its DNA-binding and transcriptional activation capacity is highly enhanced. 38 Moreover, the increased expression of a classical p53-target gene, p21 WAF1 , a cyclin-dependent kinase inhibitor, is a 'hallmark' of the initiation of the senescence programme.…”

Section: Discussionmentioning

confidence: 99%

“…19 In senescent cells, p53 exhibits an increased DNAbinding and transcriptional activity and, when overexpressed, it can induce a senescent-like phenotype. 20 Moreover, mice that express a modestly hyperactive p53 form display a premature onset of a spectrum of age-related features and reduced longevity, hence implicating p53 also in organismal aging. 21 Bearing in mind that ICAM-1 is overexpressed in senescent cells and aged tissues, 6,7,22 we explored whether p53 activation is responsible for the overexpression of ICAM-1 in cellular senescence.…”

mentioning

confidence: 99%

p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions

Gorgoulis

Pratsinis

Zacharatos

et al. 2005

Laboratory Investigation

107

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Most normal somatic cells enter a state called replicative senescence after a certain number of divisions, characterized by irreversible growth arrest. Moreover, they express a pronounced inflammatory phenotype that could contribute to the aging process and the development of age-related pathologies. Among the molecules involved in the inflammatory response that are overexpressed in senescent cells and aged tissues is intercellular adhesion molecule-1 (ICAM-1). Furthermore, ICAM-1 is overexpressed in atherosclerosis, an agerelated, chronic inflammatory disease. We have recently reported that the transcriptional activator p53 can trigger ICAM-1 expression in an nuclear factor-kappa B (NF-jB)-independent manner (Gorgoulis et al, EMBO J. 2003; 22: 1567-1578. As p53 exhibits an increased transcriptional activity in senescent cells, we investigated whether p53 activation is responsible for the senescence-associated ICAM-1 overexpression. To this end, we used two model systems of cellular senescence: (a) human fibroblasts and (b) conditionally immortalized human vascular smooth muscle cells. Here, we present evidence from both cell systems to support a p53-mediated ICAM-1 overexpression in senescent cells that is independent of NF-jB. We also demonstrate in atherosclerotic lesions the presence of cells coexpressing activated p53, ICAM-1, and stained with the senescence-associated b-galactosidase, a biomarker of replicative senescence. Collectively, our data suggest a direct functional link between p53 and ICAM-1 in senescence and age-related disorders.

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“…Mice with an overactive p53 protein, where the threshold for stress responses is lowered, die prematurely and have compromised stem cell capabilities (senescence of the stem cells). 50 These mice are more resistant to developing cancers initiated with carcinogens. These mice also die at younger ages than wild-type mice with a normal p53 protein.…”

Section: The Downstream Events In the P53 Pathwaymentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research.

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Does p53 affect organismal aging?

Cited by 141 publications

References 151 publications

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions

The P53 pathway: what questions remain to be explored?

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