Mutant p53 Protects Cells from 12-<i>O</i>-Tetradecanoylphorbol-13-Acetate–Induced Death by Attenuating Activating Transcription Factor 3 Induction

Buganim, Yosef; Kalo, Eyal; Brosh, Ran; Besserglick, Hila; Nachmany, Ido; Rais, Yoach; Stambolsky, Perry; Tang, Xiaohu; Milyavsky, Michael; Shats, Igor; Kalis, Marina; Goldfinger, Naomi; Rotter, Varda

doi:10.1158/0008-5472.can-06-0916

Cited by 32 publications

(26 citation statements)

References 45 publications

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“…It is well established that mutant p53 regulates the activities of different promoters and thus induces or represses the transcription of specific genes (4,16,39,44,52,53). Since we observed that the p53R175H mutant reduces the RNA levels of TGF-␤RII, it was important to confirm this reduction by measuring the promoter activity of this receptor in the presence of the p53R175H mutant.…”

Section: Mutant P53 Inhibits Tgf-␤1-mediated Nuclear Translocation Ofmentioning

confidence: 64%

“…These activities range from enhanced cell proliferation in culture (44,52,53) to increased tumorigenicity in vivo, as observed in a Li-Fraumeni syndrome model generated with mice (23,34), as well as enhanced resistance to a variety of anticancer drugs commonly used in clinical practice (1,3,4). These types of activities were shown to depend on the integrity of the N-terminal domain, which includes the transcriptional domain of the mutant p53 protein (31).…”

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confidence: 99%

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Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Kalo

Buganim

Shapira

et al. 2007

Molecular and Cellular Biology

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Both transforming growth factor beta (TGF-␤) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-␤ signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-␤ pathway was observed. The notion that mutant p53 interferes with the wild-type p53-induced pathway and acts by a "gain-of-function" mechanism prompted us to investigate the effect of mutant p53 on the TGF-␤-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-␤1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-␤1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus. Furthermore, we found that mutant p53 attenuates the TGF-␤1-induced transcription activity of SMAD2/3 proteins. In searching for the mechanism that underlies this attenuation, we found that mutant p53 reduces the expression of TGF-␤ receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 "gain of function" pertaining to the TGF-␤ signaling pathway.

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Section: Mutant P53 Inhibits Tgf-␤1-mediated Nuclear Translocation Ofmentioning

confidence: 64%

mentioning

confidence: 99%

Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Kalo

Buganim

Shapira

et al. 2007

Molecular and Cellular Biology

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“…3), suggesting that ATF3 might also inhibit hypertrophy via the calcium-calmodulin-PKC-class II HDACs signaling pathway. However, it remains unclear whether ATF3 can directly regulate PKC gene regulation (Buganim et al, 2006). Recent evidence shows that cardiac apoptosis, although at a low level, is present in pressure-overload cardiac hypertrophy (Teiger et al, 1996;Li et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Lin

Chen

et al. 2014

Mol Pharmacol

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Activating transcription factor 3 (ATF3), a cAMP response element-binding protein/ATF family transcription factors member, has been implicated in the cardiovascular and inflammatory system and is rapidly induced by ischemic-reperfusion injuries. We performed transverse aortic banding (TAB) experiments using ATF3 gene-deleted mice (ATF3 2/2 ) and wild-type (WT) mice to determine what effect it might have on heart failure induced by pressure overloading. Compared with the WT mice, ATF3 2/2 mice were found by echocardiography to have decreased left ventricular contractility with loss of normal cardiac hypertrophic remodeling. The ATF3 2/2 mice had greater numbers of terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive cells and higher levels of activated caspase-3, as well as more apoptosis. Restoration of ATF3 expression in the heart of ATF3 2/2 mice by adenovirus-induced ATF3 treatment significantly improved cardiac contractility after TAB. The results from molecular and biochemical analyses, including chromatin immune-precipitation and in vitro /in vivo promoter assays, showed that ATF3 bound to the ATF/cAMP response element of the Beclin-1 promoter and that ATF3 reduced autophagy via suppression of the Beclin-1-dependent pathway. Furthermore, infusion of tert-butylhydroquinone (tBHQ), a selective ATF3 inducer, increased the expression of ATF3 via the nuclear factor erythroid 2-related transcriptional factor, inhibited TABinduced cardiac dilatation, and increased left ventricular contractility, thereby rescuing heart failure. Our study identified a new epigenetic regulation mediated by the stress-inducible gene ATF3 on TAB-induced cardiac dysfunction. These findings suggest that the ATF3 activator tBHQ may have therapeutic potential for the treatment of pressure-overload heart failure induced by chronic hypertension or other pressure overload mechanisms.

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“…As 50% of human cancers harbor mutations in p53 protein (Brosh and Rotter, 2009;Buganim et al, 2006;Stambolsky et al, 2010), it is tempting to speculate that mutant p53 might be responsible for high levels of ROS observed in cancer cells. Furthermore, several studies suggest that stress induced by oxidative and nitrosative damage may cause p53 mutations at specific sites (Goodman et al, 2004;Hussain et al, 2007;Marrogi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high ROS levels

Kalo

Kogan-Sakin

Solomon

et al. 2012

Journal of Cell Science

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SummaryUncontrolled accumulation of reactive oxygen species (ROS) causes oxidative stress and induces harmful effects. Both high ROS levels and p53 mutations are frequent in human cancer. Mutant p53 forms are known to actively promote malignant growth. However, no mechanistic details are known about the contribution of mutant p53 to excessive ROS accumulation in cancer cells. Herein, we examine the effect of p53 R273H, a commonly occurring mutated p53 form, on the expression of phase 2 ROS-detoxifying enzymes and on the ability of cells to readopt a reducing environment after exposure to oxidative stress. Our data suggest that p53 R273H mutant interferes with the normal response of human cells to oxidative stress. We show here that, upon oxidative stress, mutant p53 R273H attenuates the activation and function of NF-E2-related factor 2 (NRF2), a transcription factor that induces the antioxidant response. This effect of mutant p53 is manifested by decreased expression of phase 2 detoxifying enzymes NQO1 and HO-1 and high ROS levels. These findings were observed in several human cancer cell lines, highlighting the general nature of this phenomenon. The failure of p53 R273H mutant-expressing cells to restore a reducing oxidative environment was accompanied by increased survival, a known consequence of mutant p53 expression. These activities are attributable to mutant p53 R273H gain of function and might underlie its well-documented oncogenic nature in human cancer.

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Mutant p53 Protects Cells from 12-O-Tetradecanoylphorbol-13-Acetate–Induced Death by Attenuating Activating Transcription Factor 3 Induction

Cited by 32 publications

References 45 publications

Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high ROS levels

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