Mutant p53: “gain of function” through perturbation of nuclear structure and function?

Deppert, Wolfgang; Göhler, Thomas; Koga, Hisashi; Kim, Ella

doi:10.1002/1097-4644(2000)79:35+<115::aid-jcb1134>3.3.co;2-l

Cited by 19 publications

(18 citation statements)

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“…26 Mutant p53 can act as an oncogene by binding to the nuclear matrix and to DNA at the matrix attachment regions, causing alterations in the nuclear structure and eliciting cell proliferation and enhanced tumorigenicity. 26 The degradation of the mutant protein is markedly reduced within tumor cells, which accumulate high amounts of mutated p53. A possible explanation for the correlation between the presence of TP53 mutations and tumor aggressiveness is that the mutations that lead to an oncogenic form of p53 can be selected during tumor development, conferring an advantage to tumor cell growth and/or aggressiveness.…”

Section: Tp53 Mutations' Association With Risk Factorssupporting

confidence: 91%

Section: Tp53 Mutations' Association With Risk Factorsmentioning

confidence: 99%

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TP53mutations in breast cancer tumors of patients from Rio de Janeiro, Brazil: Association with risk factors and tumor characteristics

Simão

Ribeiro

Amorim

et al. 2002

Intl Journal of Cancer

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Somatic mutations in the TP53 gene are the most frequently observed genetic alterations in human malignancies, including breast cancer, which is one of the leading causes of death among women in Brazil. In our study, we determined the frequency and the pattern of TP53 mutations in malignant breast tumors from 120 patients living in Rio de Janeiro, Brazil. TP53 mutations were found in 20% of the tumors, which contained a diversity of mutation types: missense (62.5%), nonsense (8.3%), silent (4.2%), intronic (12.5%), insertion (4.2%) and deletion (8.3%). Of a total of 15 missense mutations, 4 were observed at Arg248 and 2 at Cys242, which are directly involved in DNA binding and in zinc binding, respectively. A subgroup of 51 patients was analyzed with respect to the relation between the presence of TP53 mutations and classical risk factors and with tumor and patient characteristics. For this analysis, we used logistic regression and, in order to obtain more precise confidence intervals, they were recalculated using a bootstrap resampling technique. Our results demonstrate that these mutations are not statistically associated with the risk factors or the patients' characteristics. However, the presence of TP53 mutations is strongly associated with the aggressiveness of the tumors, measured by Elston classification (OR ‫؍‬ 11.97 and 95% CI of 2.24 -307.05). This finding is in agreement with previous studies, which report the presence of TP53 mutations in tumors with poor prognosis. This correlation between tumor aggressiveness and TP53 mutations could be a crucial variable for the treatment and prognosis of breast cancer. © 2002 Wiley-Liss, Inc. Key words: TP53 gene; breast cancer; risk factors; clinicopathologic features; Rio de Janeiro, Brazil; Elston gradeBreast cancer is one of the leading causes of death among women in Brazil. The Brazilian expected mortality rate for 2001 is 9.9 women per 100,000, whereas the highest incidence was estimated to be in the State of Rio de Janeiro: 82 women per 100,000. 1 The etiology of breast cancer is rather complex and, although 10 -15% of the patients have a family history of the disease, only a small proportion can be explained by mutations in genes such as BRCA1 and BRCA2.The different geographic distribution of cases and evidence from migration studies suggest that some environmental and/or lifestyle factors may be related to the development of breast cancer. 2 Reproductive history, family history of breast cancer, cigarette smoking and alcohol consumption are generally cited as risk factors of breast cancer. However, how these factors contribute to trigger the molecular mechanisms of tumor initiation and progression is not completely understood. 3 Mutations in the tumor suppressor gene, TP53, are the most common genetic alterations seen in human cancer. 4 This gene encodes a 393 amino acid nuclear phosphoprotein that acts as a transcription factor and is implicated in nearly all pathways involved in cell proliferation control: modulation of cell-cycle progression, apopto...

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Section: Tp53 Mutations' Association With Risk Factorssupporting

confidence: 91%

Section: Tp53 Mutations' Association With Risk Factorsmentioning

confidence: 99%

TP53mutations in breast cancer tumors of patients from Rio de Janeiro, Brazil: Association with risk factors and tumor characteristics

Simão

Ribeiro

Amorim

et al. 2002

Intl Journal of Cancer

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“…WT was pan-nuclear, whereas HcRed-p53 A138V formed aggregates within the inner nuclear membrane consistent with previous reports of MTp53 proteins binding to the nuclear matrix (50). HcRed alone was almost always cytoplasmic at either temperature.…”

Section: Expression Of Wtp53 or P53mentioning

confidence: 99%

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

Cuddihy

Jalali

Coackley

et al. 2008

Molecular Cancer Therapeutics

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New molecular cancer treatment strategies aim to reconstitute wild-type p53 (WTp53) function in mutant p53 (MTp53) -expressing tumors as a means of resensitizing cells to chemotherapy or radiotherapy. The success of this approach may depend on whether MTp53 proteins are acting in a dominant-negative or independent gain-offunction mode. Herein, we describe an isogenic, temperature-sensitive p53 model (p53 A138V

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“…Several recent studies have shown that the majority of mutant p53 proteins presents varying degrees of residual transactivation activity, which could account for the great phenotypic diversity of the behavior of tumors in response to therapy (Kato et al, 2003;Resnick and Inga, 2003). It has also been shown that some mutant p53 proteins could acquire the capacity to recognize new DNA sequences, such as nuclear matrix attachment region sequences (MARs) (Muller et al, 1996;Deppert et al, 2000). In order to validate this high-throughput SPR imaging approach to a biological problem, we used this technique to simultaneously study the interactions between p53 and five different DNA sequences.…”

Section: Published Online 7 June 2004mentioning

confidence: 99%

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

et al. 2004

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The greatest challenge in the postgenomic era is the description of proteome interactions, such as protein-protein or protein-DNA interactions. Surface plasmon resonance (SPR) is an optical technique in which binding of an analyte to the surface changes the refractive index at the surface/solution interface. Molecular interactions are analysed in real time without a labeling step. Currently, the limit to SPR imaging is the small number of reactions that can be simultaneously analysed. Using a novel grafting technology and a new imaging system, we increased the throughput of SPR imaging. The interaction between p53 and DNA was chosen as a paradigm for validation of this assay. Using a tagged DNA methodology, we simultaneously targeted multiple DNA sequences on a single chip. The interaction between p53 and these DNA sequences was monitored by SPR imaging. Qualitative and quantitative analysis provides results similar to those obtained with conventional technologies.

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Mutant p53: “gain of function” through perturbation of nuclear structure and function?

Cited by 19 publications

References 0 publications

TP53mutations in breast cancer tumors of patients from Rio de Janeiro, Brazil: Association with risk factors and tumor characteristics

TP53mutations in breast cancer tumors of patients from Rio de Janeiro, Brazil: Association with risk factors and tumor characteristics

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

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