Negative Control of p53 by Sir2α Promotes Cell Survival under Stress

Luo, Jianyuan; Nikolaev, Anatoly; Imai, Shoichi; Chen, Delin; Su, Fei; Shiloh, Ariel; Guarente, Leonard; Gu, Wei

doi:10.1016/s0092-8674(01)00524-4

Cited by 1,973 publications

(1,774 citation statements)

References 48 publications

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“…At low levels of transfected p300, hAda3 enhanced p53 acetylation as detected by panacetylated p53 (Luo et al, 2001) and acetylated Lys-382 p53 (Ac-K382-p53) antibodies ( Figure 1a, lanes 2-5). The Ac-K382-p53 antibody produced stronger signals and was subsequently used for detection of acetylation of endogenous p53.…”

Section: Resultsmentioning

confidence: 99%

“…After 24 h cells were harvested and lysed in Flag buffer (Luo et al, 2001) supplemented with complete protease inhibitor (Roche, Nutley, NJ, USA), 10 mM trichostatin A and 5 mM nicotinamide (Sigma Aldrich, St Louis, MO, USA). Cell lysates containing 50 mg protein were separated by sodium dodecyl sulfate-polyacrylamide gel Figure 6 Model of hAda3 role in p14ARF-p53 signaling.…”

Section: Protein Detectionmentioning

confidence: 99%

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hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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Acetylation is thought to be a key event for p53 activation. We demonstrate that p14ARF-induced senescence of human mammary epithelial cells (MEC) is associated with p53 acetylation and requires hAda3, a component of histone acetyltransferase complexes and a p53 transcriptional coactivator. Expression of the N-terminal domain of hAda3 that binds p53 but not p300 blocked p14ARF-induced p53 acetylation and protected MECs from senescence. Consistent with these findings, the human papillomavirus 16 E6 mutant Y54D, which selectively targets hAda3 but not p53 for degradation and protects MECs from p14ARF-induced senescence, inhibited p53 acetylation. In H1299 cells, hAda3 overexpression increased p300-mediated p53 acetylation, which conversely decreased following small interfering RNA (siRNA) knockdown of hAda3. Moreover, depletion of hAda3 by siRNA inhibited endogenous p53 acetylation and accumulation of p21cip1 in response to ectopic p14ARF. These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence.

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Section: Resultsmentioning

confidence: 99%

Section: Protein Detectionmentioning

confidence: 99%

hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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“…17 hSir2 inhibits p53 activity through deacetylation of Lys382 and antagonises genotoxic stress-induced apoptosis. 145,146 The localisation of CBP and hSir2 to PML-NBs, two factors that exert antagonistic functions on p53 activity, suggest a potential mechanism for the regulation of p53 function in PML-NBs the change of its acetylation status, depending on the molecular context and stimulus. In addition, a fraction of the p53 degrading E3 ubiquitin ligase Hdm2 (human Mdm2) was found associated with PML-NBs.…”

Section: Regulation Of P53 Activity In Pml-nbsmentioning

confidence: 99%

Body language: the function of PML nuclear bodies in apoptosis regulation

2003

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Promyelocytic leukaemia (PML) nuclear bodies (NBs) are macromolecular nuclear domains present in virtually every mammalian cell. PML nuclear bodies (PML-NBs) were functionally linked to various fundamental cellular processes, including transcriptional control, tumour suppression and apoptosis regulation. Supporting the important function of PML and its associated NBs in apoptosis regulation, several apoptotic regulators localise to PML-NBs, and cells from PMLdeficient mice show severe apoptotic defects, including induction of genotoxic stress and death receptor CD95 (Fas/ APO-1) activation. Based on the current literature, we hypothesise that PML-NBs regulate apoptosis through different molecular mechanisms, on the one hand by acting as macromolecular scaffolds for recruitment and post-translational modification of the apoptotic key regulator p53, and on the other by regulating the subcellular bioavailability and quality of some apoptotic signal transducers.

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“…SIRT1 is a nicotinamide adenine dinucleotide (NAD+)‐dependent deacetylase that catalyzes the removal of acetyl groups from lysine residues on histone proteins, resulting in gene silencing (Braunstein, Rose, Holmes, Allis, & Broach, 1993; Imai, Armstrong, Kaeberlein, & Guarente, 2000; Tanny, Dowd, Huang, Hilz, & Moazed, 1999). SIRT1 also deacetylates transcription factors including PGC1α, which induces mitochondrial oxidative phosphorylation (Lagouge et al, 2006), p53, which promotes cell survival (Luo et al, 2001; Vaziri et al, 2001) and triggers adaptation to calorie restriction with its accompanying stress resistance (Guarente, 2013). Through these actions, SIRT1 functions to maintain cellular homeostasis and thereby prevent age‐related pathological changes.…”

Section: Introductionmentioning

confidence: 99%

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

et al. 2018

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SIRT1 is an NAD+‐dependent deacetylase that functions in a variety of cells and tissues to mitigate age‐associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild‐type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age‐related degeneration of motor neurons’ presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end‐stage disease in high copy SOD1G93A mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.

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Negative Control of p53 by Sir2α Promotes Cell Survival under Stress

Cited by 1,973 publications

References 48 publications

hAda3 regulates p14ARF-induced p53 acetylation and senescence

hAda3 regulates p14ARF-induced p53 acetylation and senescence

Body language: the function of PML nuclear bodies in apoptosis regulation

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

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