Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm

Université P.M. Curie, 4 place Jussieu, 75005 Paris, France.
Cancer Cell (Impact Factor: 23.52). 11/2007; 12(4):303-12. DOI: 10.1016/j.ccr.2007.10.001
Source: PubMed


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,
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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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    • "Intriguingly, a G>A mutation at codon 273 (R273H) was found in NNK transformed cells. The missense mutation R273H belongs to the most prominent mutation hot-spots in the TP53 gene and alters the target DNA sequence [37]. It has been reported that the DNA-contact mutant R273H can exert dominant negative effects on the wild-type p53 protein by heterooligomerization and has compromised transactivity of downstream target genes, such as p21 (CDKN1A) [38–41]. "
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    • "The importance of the MDM2–p53 interaction is underscored by work demonstrating that Mdm2 −/− mice are embryonic lethal but are rescued by concomitant deletion of p53 [98]. Negative regulators of p53 function, such as MDM2, are classified as proto-oncogenes and lead to constitutive inhibition of p53 thereby promoting cancer without a need to alter the p53 gene itself [99]. Thus, it is important that additional tumor suppressors are present to ensure that the negative regulators of p53 are inhibited. "
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