hADA3 is required for p53 activity

Wang, Ting; Kobayashi, Takahiko; Takimoto, Rishu; Denes, Alec E.; Snyder, Eric L.; El‐Deiry, Wafik S.; Brachmann, Rainer K.

doi:10.1093/emboj/20.22.6404

Cited by 89 publications

(98 citation statements)

References 45 publications

(105 reference statements)

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“…hAda3 regulates p300-mediated p53 acetylation The hAda3 protein complexes with both p53 and p300 and enhances p53 transcriptional activity (Wang et al, 2001;Kumar et al, 2002). We confirmed hAda3 binding to p53 by coimmunoprecipitation of Flag-hAda3 and p53 following transfection into p53 null human H1299 cells.…”

Section: Resultssupporting

confidence: 59%

“…We confirmed hAda3 binding to p53 by coimmunoprecipitation of Flag-hAda3 and p53 following transfection into p53 null human H1299 cells. While chemical cross-linking was previously required to detect their association (Wang et al, 2001), this step was not necessary in our experiments (Supplementary Information Figure 1). Interestingly, inclusion of HDM2 did not reduce Flag-hAda3 coimmunoprecipitation with p53.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we used a different approach to selectively inactivate hAda3. Because transient overexpression of the N-terminal domain of hAda3 (N-hAda3) protected U2OS cells from UV-induced apoptosis (Wang et al, 2001), we tested whether stable expression of N-hAda3 would protect hTERT-MEC from p14ARF-induced senescence.…”

Section: Resultsmentioning

confidence: 99%

“…hAda3 is a 432 amino acid (aa) protein; the N-terminal domain of hAda3 (aa 1-214) binds p53 while the C-terminal domain (aa 215-432) interacts with components of the HAT complex (Wang et al, 2001). hAda3 appears to be required for p53-mediated transcriptional activation and apoptosis (Wang et al, 2001;Kumar et al, 2002).…”

Section: Introductionmentioning

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: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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“…Recent studies of ADA2a and ADA2b in higher eukaryotes, including mammals, have demonstrated that these proteins assemble into multiple complexes that vary considerably. In addition, hADA3 also participates in these complexes and associates with p53; hADA3 overexpression increases the transcriptional activity of p53 by affecting p53 acetylation [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

The role of human ADA2a in the regulation of p53 acetylation and stability

et al. 2011

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The tumor suppressor protein p53 is a well-known transcription factor that functions as a critical component of the genotoxic stress response via regulating the expression of effector proteins that control cellular fate following DNA damage. The human p300/CBP-associated factor (PCAF)-containing histone acetyltransferase (HAT) complex is important for the stability and activity of p53 via its acetylation. The human homolog of yeast alteration/deficiency in activation 2a (ADA2a) is a stable component of the human PCAF-containing HAT complex. In this study, we demonstrated that p53 and hADA2a physically interact with each other in human HEK 293T cells. Using overexpression and small interfering RNA-mediated knockdown, we demonstrated that hADA2a stabilizes p53 via promoting its acetylation at lysine 320 -a PCAF-dependent acetylation site. Furthermore, hADA2a can potentiate the transcriptional activity of p53 at the BAX and p21 promoters to induce cell apoptosis and cell cycle arrest. Overall, our results establish that hADA2a, a component of the PCAF-containing histone acetyltransferase co-activator complex, is a mediator of acetylation-dependent stabilization and activation of p53 in mammalian cells. hADA2a, p53, acetylation, PCAF Citation:Huang J, Zhang L, Xiao L, et al. The role of human ADA2a in the regulation of p53 acetylation and stability.

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Chromatin Remodeling in Carcinoma Cells

Becker

2012

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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hADA3 is required for p53 activity

Cited by 89 publications

References 45 publications

hAda3 regulates p14ARF-induced p53 acetylation and senescence

hAda3 regulates p14ARF-induced p53 acetylation and senescence

The role of human ADA2a in the regulation of p53 acetylation and stability

Chromatin Remodeling in Carcinoma Cells

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