Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

Kogan-Sakin, Ira; Tabach, Yuval; Buganim, Yossi; Molchadsky, Alina; Solomon, Hilla; Madar, Shalom; Kamer, Iris; Stambolsky, Perry; Shelly, Asha; Goldfinger, Naomi; Valsesia‐Wittmann, Sandrine; Puisieux, Alain; Zundelevich, Adi; Gal‐Yam, Einav Nili; Avivi, Camilla; Barshack, Iris; Brait, Mariana; Sidransky, David; Domany, Eytan; Rotter, Varda

doi:10.1038/cdd.2010.94

Cited by 139 publications

(111 citation statements)

References 25 publications

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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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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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“…Other mechanisms of mutant p53 GOF include mutant-p53 complexes with Smad that fuel TGF-β-induced metastasis (7) and integrin recycling (8). Additionally, mutant p53 interacts with the vitamin D receptor and converts vitamin D into an antiapoptotic agent (9)(10)(11)(12)(13)(14). More recently, mutant p53 was reported to form transcriptional complexes on promoters of genes encoding several enzymes of the Mevalonate pathway, which increases metastasis of breast cancer cells (9).…”

mentioning

confidence: 99%

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Xiong¹,

Tu²,

Kollareddy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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p53 R172H/+ mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53 +/− mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53 R172H/+ mice with metastasis to osteosarcomas from p53 +/− mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53 R172H/+ osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformationspecific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis. mammary tumor | fatty acid metabolism T he p53 tumor suppressor pathway is inactivated in ∼50% of human cancers (http://p53.iarc.fr). Missense mutations in particular account for 80% of p53 alterations, suggesting that mutant p53 proteins provide additional advantages for tumor cell growth (1). Li-Fraumeni syndrome patients with p53 missense mutations have a higher cancer incidence and an earlier age of tumor onset than individuals with truncating or splicing mutations (2). p53 knockin mice show a gain-of-function (GOF) phenotype in vivo, with high metastatic capacity compared with mice inheriting a p53-null allele (3, 4). GOF activities of mutant p53 are mediated by suppression of the p53 family members, p63 and p73 (3-6). Other mechanisms of mutant p53 GOF include mutant-p53 complexes with Smad that fuel TGF-β-induced metastasis (7) and integrin recycling (8). Additionally, mutant p53 interacts with the vitamin D receptor and converts vitamin D into an antiapoptotic agent (9-14). More recently, mutant p53 was reported to form transcriptional complexes on promoters of genes encoding several enzymes of the Mevalonate pathway, which increases metastasis of breast cancer cells (9). These data suggest multiple pathways contribute to the GOF phenotypes of cells with mutant p53. Although mutant p53 lacks sequencespecific DNA binding activity, its interaction with other transcriptional factors or the components of basic transcriptional machinery allow it to modulate gene expression (15). ChIP-onchip and ChIP-sequencing techniques show that mutant p53 affects transcription of many genes (9, 13, 16, 17).In this study, expression array analyses identified gene differences between p53 R172H/+ m...

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“…Indeed, mutp53 contributes to induction of EMT over several passages by alleviation of the epigenetic repression of TWIST1, a master regulator of EMT. 9 Furthermore, mutp53 strongly enhances reprogramming efficiency and can replace one of the classical reprogramming factors, but the resulting cells are highly tumorigenic. 57 The "epigenetic alteration of transcription" by mutp53 would very likely be intrinsically stochastic due to slight differences in the transcriptional status of single cells.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Expression of mutp53 increases drug resistance 7 and enhances the potential for the outgrowth of singularized cells. 8 Furthermore, mutp53 promotes the transition from an epithelial to a mesenchymal differentiation state, 9 a process that is functionally linked to invasive growth and metastatic dissemination, 10 and the generation of a cellular subset that behaves like cancer stem cells (CSCs) within epithelial tumors. 11 These data provide a link between stem-like properties of tumor cells and mutp53 function.…”

Section: Mutant P53 Is a Transcriptional Co-factor That Binds To G-rimentioning

confidence: 99%

Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity

et al. 2012

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Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

Cited by 139 publications

References 25 publications

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

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

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity

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