Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm

Université P.M. Curie, 4 place Jussieu, 75005 Paris, France.
Cancer Cell (Impact Factor: 23.89). 11/2007; 12(4):303-12. DOI: 10.1016/j.ccr.2007.10.001
Source: PubMed

ABSTRACT p53 mutations are found in 50% of human cancers. Molecular epidemiology has shown strong correlations between the spectrum of p53 mutations and exposure to exogenous carcinogens. This spectrum is influenced quantitatively and qualitatively by various upstream genetic filters that modulate carcinogen activation, detoxification, and/or DNA repair. In this review, we will discuss how other factors such as tissue specificity, SNP of genes associated with the p53 pathway, other genetic alterations, or p53 mutant heterogeneity can act as a second set of downstream filters that also have a profound impact on the spectrum of p53 mutations.

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Available from: Klas G Wiman, Aug 01, 2015
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    • "On the other hand, p53 has been reported to be a potential candidate for cardiac dysfunction. Also, p53 null mice showed successful regression of cardiac hypertrophy [16] but led to ectodermal tumorigenesis in such animals [17]. The bioactive macromolecular drug and p53 siRNA were selected as test molecules in our study encapsulated by the nano-construct for cardiac selective delivery and efficient regression of pathological hypertrophy without bystander effect. "
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    ABSTRACT: Diverse array of therapeutic regimens, drugs or siRNA, are commonly used to regress cardiac hypertrophy, although, bystander effect and lower retention of bioactive molecules significantly reduce their functional clinical efficacy. Carvedilol, a widely used and effective anti-hypertrophic drug, simultaneously blocks β-adrenergic receptors non-specifically in various organs. Likewise, non-specific genome-wide downregulation of p53 expression by specific siRNA efficiently abrogates cardiac hypertrophy but results in extensive tumorigenesis affecting bystander organs. Therefore, delivery of such therapeutics had been a challenge in treating cardiovascular dysfunction. Cardiac tissue engineering was successfully accomplished in this study, by encapsulating such bioactive molecules with a stearic acid modified Carboxymethyl chitosan (CMC) nanopolymer conjugated to a homing peptide for delivery to hypertrophied cardiomyocytes in vivo. The peptide precisely targeted cardiomyocytes while CMC served as the vector mediator to pathological myocardium. Controlled delivery of active therapeutic payloads within cardiomyocytes resulted in effective regression of cardiac hypertrophy. Thus, this novel nano-construct as a spatio-temporal vector would be a potential tool for developing effective therapeutic strategies within cardiac micro-environment via targeted knockdown of causal genes.
    Journal of Controlled Release 01/2015; 200C(2015). DOI:10.1016/j.jconrel.2015.01.008 · 7.26 Impact Factor
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    • "The TP53 gene is frequently mutated in many types of cancer, and most of these mutations occurred within the DBD [52]. Because we identified that VRK1 binds to p53 through this region we analysed whether some of these common p53 mutations [53] affected its binding to VRK1. "
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    ABSTRACT: DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. VRK1physically interactswithp53byanti bait coimmunoprecipitation(1,2,3,4) VRK1physically interactswithp53bypull down(1,2,3).
    FEBS letters 01/2014; 588(5). DOI:10.1016/j.febslet.2014.01.040 · 3.34 Impact Factor
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    • "In response to ionizing radiation, MDM2 undergoes rapid ATM-dependent phosphorylation prior to p53 accumulation. The increase in MDM2 basal levels induces degradation and blockade of transcriptional activity of p53 protein [14] [15]. The functional p53 polymorphism, characterized by C>G change at the second position of codon 72 (rs1042522), results in Arg>Pro amino acid substitution. "
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    ABSTRACT: The purpose of this study was to evaluate the association between ATM, TP53 and MDM2 polymorphisms in prostate cancer patients and morbidity after radiotherapy. The presence of ATM (rs1801516), TP53 (rs1042522, rs1800371, rs17878362, rs17883323, and rs35117667), and MDM2 (rs2279744) polymorphisms was assessed by direct sequencing of PCR fragments from 48 patients with histologically proven prostate adenocarcinoma and treated with external beam radiation. The side effects were classified according to the Radiation Therapy Oncology Group (RTOG) score. The results showed no association between clinical characteristics and the development of radiation toxicities (P > 0.05). The C>T transition in the position 16273 (intron 3) of TP53 (rs35117667) was significantly associated with the risk of acute skin toxicity (OR: 0.0072, 95% CI 0.0002-0.227, P = 0.003). The intronic TP53 polymorphism at position 16250 (rs17883323) was associated with chronic urinary toxicity (OR: 0.071, 95%CI 0.006-0.784, P = 0.032). No significant associations were found for the remaining polymorphisms (P > 0.05). The results show that clinical characteristics were not determinant on the developing of radiation sensitivity in prostate cancer patients, and intronic TP53 polymorphisms would be associated with increased acute and chronic radiation toxicities. These observations corroborate the importance of investigating the genetic profile to predict adverse side effects in patients undergoing radiotherapy.
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