共查询到20条相似文献,搜索用时 437 毫秒
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Role of NF-kappaB in p53-mediated programmed cell death 总被引:26,自引:0,他引:26
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Regulation of p53 activity through lysine methylation 总被引:1,自引:0,他引:1
Chuikov S Kurash JK Wilson JR Xiao B Justin N Ivanov GS McKinney K Tempst P Prives C Gamblin SJ Barlev NA Reinberg D 《Nature》2004,432(7015):353-360
p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase. 相似文献
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Jing Nie Lin Liu XiaoHang Zhao Ping Xie PingKun Zhou GuiChun Xing XiangJun Liu FuChu He WeiDong Han LingQiang Zhang 《科学通报(英文版)》2011,56(30):3155-3161
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is
tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading
to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes
p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53.
However, it is unclear how the Smurf1-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in
response to etoposide treatment Smurf1 dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The
negative regulation of Smurf1 on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response,
implicating high expression of Smurf1 might confer the resistance against p53 activation. Consistent with this notion, we
observed that Smurf1/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer
tissues, suggesting the oncogenic tendency of Smurf1/2. 相似文献
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The tumour-suppressor gene p53 is frequently mutated in human cancers and is important in the cellular response to DNA damage. Although the p53 family members p63 and p73 are structurally related to p53, they have not been directly linked to tumour suppression, although they have been implicated in apoptosis. Given the similarity between this family of genes and the ability of p63 and p73 to transactivate p53 target genes, we explore here their role in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for one or a combination of p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene. While using the E1A system facilitated our ability to perform biochemical analyses, we also examined the functions of p63 and p73 using an in vivo system in which apoptosis has been shown to be dependent on p53. Using both systems, we show here that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage. 相似文献
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The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response 总被引:11,自引:0,他引:11
Zheng H You H Zhou XZ Murray SA Uchida T Wulf G Gu L Tang X Lu KP Xiao ZX 《Nature》2002,419(6909):849-853
p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis. It is well documented that DNA damage leads to phosphorylation and activation of p53 (refs 1-3), yet how p53 is activated is still not fully understood. Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase. Furthermore, the interaction of Pin1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53. The Pin1-mediated p53 activation requires the WW domain, a phosphorylated Ser/Thr-Pro motif interaction module, and the isomerase activity of Pin1. Moreover, Pin1-deficient cells are defective in p53 activation and timely accumulation of p53 protein, and exhibit an impaired checkpoint control in response to DNA damage. Together, these data suggest a mechanism for p53 regulation in cellular response to genotoxic stress. 相似文献
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Wild-type p53 activates transcription in vitro. 总被引:70,自引:0,他引:70
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Inhibition of JNK activation through NF-kappaB target genes. 总被引:26,自引:0,他引:26
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The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults 总被引:5,自引:0,他引:5
Zacchi P Gostissa M Uchida T Salvagno C Avolio F Volinia S Ronai Z Blandino G Schneider C Del Sal G 《Nature》2002,419(6909):853-857
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Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions 总被引:5,自引:0,他引:5
Gorgoulis VG Vassiliou LV Karakaidos P Zacharatos P Kotsinas A Liloglou T Venere M Ditullio RA Kastrinakis NG Levy B Kletsas D Yoneta A Herlyn M Kittas C Halazonetis TD 《Nature》2005,434(7035):907-913
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations. 相似文献
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The p66shc adaptor protein controls oxidative stress response and life span in mammals 总被引:44,自引:0,他引:44
Migliaccio E Giorgio M Mele S Pelicci G Reboldi P Pandolfi PP Lanfrancone L Pelicci PG 《Nature》1999,402(6759):309-313
Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals. 相似文献
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Laurie NA Donovan SL Shih CS Zhang J Mills N Fuller C Teunisse A Lam S Ramos Y Mohan A Johnson D Wilson M Rodriguez-Galindo C Quarto M Francoz S Mendrysa SM Guy RK Marine JC Jochemsen AG Dyer MA 《Nature》2006,444(7115):61-66
Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma. 相似文献
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Downstream nuclear events in brassinosteroid signalling 总被引:2,自引:0,他引:2
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