p53 Regulates the Ras Circuit to Inhibit the Expression of a Cancer-Related Gene Signature by Various Molecular Pathways

Buganim, Yosef; Solomon, Hilla; Rais, Yoach; Kistner, Daria; Nachmany, Ido; Brait, Mariana; Madar, Shalom; Goldstein, Ido; Kalo, Eyal; Adam, Nitzan; Gordin, Maya; Rivlin, Noa; Kogan, Ira; Brosh, Ran; Sefadia-Elad, Galit; Goldfinger, Naomi; Sidransky, David; Kloog, Yoel; Rotter, Varda

doi:10.1158/0008-5472.can-09-2661

Cited by 67 publications

(74 citation statements)

References 44 publications

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“…Indeed, p53 mutation has been shown to occur relatively late during multistage oncogenic progression and often follows Ras mutation-induced ERK signaling (44). It has been shown that mp53 works together with oncogenic Ras to induce the expression of several protumorigenesis and prometastasis genes in gene expression profiling studies (45). Our finding that mp53 repressed the oncogenic role of TGF-␤ in the model systems we used suggests that additional signaling activation and genetic alterations such as ERK signaling activation and attenuation of TGF-␤-induced growth inhibition appear necessary to collaboratively confer the tumor-promoting activity of mp53 and TGF-␤ during cancer progression.…”

Section: Discussionmentioning

confidence: 61%

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 61%

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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“…29,30 ATF3 directly binds to the CGS promoters and represses their expression, while BTG2 interacts with H-Ras and represses its activity. 31 This effect may represent a novel suppressive function of wild-type p53. These findings are supported by reports showing that pro-malignant genes are upregulated following p53 loss and acquisition of activated Ras.…”

Section: The P53 Pathway: From Normal To Tumor Cellsmentioning

confidence: 96%

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

et al. 2010

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Three decades of p53 research have led to many advances in understanding the basic biology of normal and cancer cells. Nonetheless, the detailed functions of p53 in normal cells, and even more so in cancer cells, remain obscure. A major breakthrough is the realization that mutant p53 has a life of its own: it contributes to cancer not only through loss of activity, but also through gain of specific 'mutant functions'. This new focus on mutant p53 is the rationale behind the meeting series dedicated to advances on mutant p53 biology. This review provides an overview of results presented at the Fourth International Workshop on Mutant p53, held in Akko, Israel in March 2009. New roles and functions of p53 relevant for tumor suppressions were presented, including the regulation of microRNAs networks, the modulation of cell-stroma interactions and the induction of senescence. A main focus of the meeting was the rapidly growing body of knowledge on autonomous properties of mutant p53 and on their oncogenic 'gain of function' impact. Importantly, the meeting highlighted that, 30 years after p53 discovery, research on mutant p53 is entering the clinical and translational era. Two major steps forward in this respect are a better understanding of the active mechanism of small drugs targeting mutant p53 in tumor cells and an improved definition of the prognostic and predictive value of mutant p53 in human cancer.

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“…Most of these mutations simultaneously lead to both loss of wild-type p53 tumor-suppressive activity and acquisition of new functions actively promoting malignant transformation. These oncogenic activities, known as mutant p53 ''gain of function'' may lead to enhanced cell proliferation, invasiveness, metastasis and resistance to a variety of anti-cancer drugs (Brosh and Rotter, 2009;Buganim et al, 2010;Kogan-Sakin et al, 2011;Muller et al, 2009;Stambolsky et al, 2010;Stambolsky et al, 2010). In the current study, we aimed to investigate how a hotspot p53 R273H mutation, known to possess oncogenic gain of function, affects cellular response to oxidative stress and expression of antioxidant defense enzymes.…”

Section: Introductionmentioning

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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p53 Regulates the Ras Circuit to Inhibit the Expression of a Cancer-Related Gene Signature by Various Molecular Pathways

Cited by 67 publications

References 44 publications

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

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

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