Transcription regulation by mutant p53

Weisz, Lilach; Oren, Moshe; Rotter, Varda

doi:10.1038/sj.onc.1210294

Cited by 181 publications

(157 citation statements)

References 82 publications

(119 reference statements)

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“…Point mutations in the tumour suppressor p53 are a common event in cancer development. The recent therapeutic strategies have essentially aimed to reconstitute the wild-type p53 function or to abolish the newly acquired oncogenic activities that promote tumour growth and support resistance to chemotherapies (Strano et al, 2007;Weisz et al, 2007;Xu, 2008). Once again, by the simple culture of yeast-expressing p53 mutants on minimal media, the yeast model offers the opportunity to screen for new intragenic mutations that inactivate wild and mutant types of p53.…”

Section: Selection Of Inactive P53 In Yeast 449mentioning

confidence: 99%

“…The mutations are scattered along the entire gene, with a strong predominance in the DNA-binding domain (Petitjean et al, 2007). In contrast to other tumour suppressor genes that are mainly altered by truncating mutations, the majority of p53 mutations are missense substitutions (75%), most of which (97%) occur in the sequence-specific DNA-binding domain (Weisz et al, 2007), with six hot-spot mutants identified in human tumours (R175, G245, R248, R249, R273 and R282). The p53 mutants fall roughly into two classes: 'DNA contact mutants', which alter the amino acid (aa) residues responsible for forming sequence-specific contacts with DNA (R248 and R273); and 'structural mutants', which disrupt the global conformation of p53 (G245, R249 and R282) (Bullock and Fersht, 2001;Cho et al, 1994;Joerger et al, 2005;Penka et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Selection of cell death‐deficient p53 mutants in Saccharomyces cerevisiae

Yacoubi

Smaoui

Belguith

et al. 2009

Yeast

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The budding yeast Saccharomyces cerevisiae is a useful system for the detection and transcriptional evaluation of mutant p53 in cancer. In previous work we showed that the overexpression of wild-type p53 induces yeast cell death on minimal medium; however, the R248W p53 mutant was completely inactive, and we suggested that ROS production is a key event in p53-induced yeast cell death. In this study we explored the effect of other p53 mutants, such as the hot-spot mutant R282W and the double mutant N268S::I332V. Unexpectedly, both mutants behaved inversely to R248W, as they completely inhibited yeast growth on minimal medium and induced ROS production. This phenotype 'yeast cell death on minimal medium' allowed for the subsequent screening of intragenic p53-inactivating mutations. In all cases, the 'revertant yeast clones' display a complete p53 inactivation through either gross deletion or nonsense mutations. More interestingly, missense mutations were also found: the deletion of I255 or substitution of R337G completely inactivated the p53 mutant R282W in the yeast context. Taken together, these results suggest that p53 tumour-derived mutants could be classified according to their ability to induce yeast cell death and not uniquely by their transcriptional activity on a selected target reporter gene.

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Section: Selection Of Inactive P53 In Yeast 449mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selection of cell death‐deficient p53 mutants in Saccharomyces cerevisiae

Yacoubi

Smaoui

Belguith

et al. 2009

Yeast

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“…5,6,10,26,27 There is no exhaustive knowledge allowing a functional classification of mutant p53 proteins that might predict the degree of gain of function activity and consequently its impact on clinical outcome. Furthermore, we provide evidence supporting that the molecular target of SIMPs activity is the disassembling of the protein complex mutantp53/p73.…”

Section: Discussionmentioning

confidence: 99%

“…6,[8][9][10] The second one is based on the possibility that mutant p53 protein can physically interact, sequester and inactivate proteins whose activities are strictly related to antitumoral effects. Protein complexes involving mutant p53 and p73 are readily detectable in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs

Agostino¹,

Cortese²,

Monti³

et al. 2008

Cell Cycle

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Many in vitro and in vivo evidence have shown that the status of p53 is a key determinant in the response of tumor cells to anticancer treatment. Here we provide evidence that peptide-mediated targeting of the protein complex mutantp53/p73 enhances the response of mutant p53 tumor cells to commonly used anticancer drugs. Indeed, we show that the disruption of the protein complex mutantp53/p73 and the consequent restoration of p73 transcriptional effects, through the activity of short interfering peptides, render mutant p53 cells more prone to the killing of adriamycin and cisplatin. Of note, the activity of the short interfering peptides is mutant p53 specific and causes no effects on wt-p53 and p53 null cells. Our findings highlight the protein complex mutantp53/ p73 as a molecular target, whose successful overriding through the selective activity of small interfering peptides, might contribute to the optimization of mutant p53 tumor treatments.

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“…The p53 controls the development of cancerous cell and suppresses tumor development which is the basic characteristic of tumor suppressor. p53 was first discovered in 1979 as the main interacting partner of the viral SV40 T-antigen (Chang et al, 1979;Kress et al, 1979;Lane and Crawford, 1979;Linzer and Levine, 1979), and rose to reputation of a tumor suppressor gene in late 1980s (Weisz et al, 2007). Since then, p53 has been one of the most intensively studied proteins worldwide, it is mainly due to the evidence that most of human malignancies bear the abovementioned alterations in its signaling pathway.…”

mentioning

confidence: 99%