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.

Download full-text


Available from: Klas G Wiman
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2015 · Journal of Controlled Release
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome integrity is essential for normal cellular functions and cell survival. Its instability can cause genetic aberrations and is considered as a hallmark of most cancers. To investigate the carcinogenesis process induced by tobacco-specific carcinogen NNK, we studied the dynamic changes of two important protectors of genome integrity, p53 and MMR system, in malignant transformation of human bronchial epithelial cells after NNK exposure. Our results showed that the expression of MLH1, one of the important MMR proteins, was decreased early and maintained the downregulation during the transformation in a histone modification involved and DNA methylation-independent manner. Another MMR protein PMS2 also displayed a declined expression while being in a later stage of transformation. Moreover, we conducted p53 mutation analysis and revealed a mutation at codon 273 which led to the replacement of arginine by histidine. With the mutation, DNA damage-induced activation of p53 was significantly impaired. We further reintroduced the wild-type p53 into the transformed cells, and the malignant proliferation can be abrogated by inducing cell cycle arrest and apoptosis. These findings indicate that p53 and MMR system play an important role in the initiation and progression of NNK-induced transformation, and p53 could be a potential therapeutic target for tobacco-related cancers.
    Full-text · Article · Aug 2014 · BioMed Research International
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since its discovery close to twenty years ago, the ARF tumor suppressor has played a pivotal role in the field of cancer biology. Elucidating ARF’s basal physiological function in the cell has been the focal interest of numerous laboratories throughout the world for many years. Our current understanding of ARF is constantly evolving to include novel frameworks for conceptualizing the regulation of this critical tumor suppressor. As a result of this complexity, there is great need to broaden our understanding of the intricacies governing the biology of the ARF tumor suppressor. The ARF tumor suppressor is a key sensor of signals that instruct a cell to grow and proliferate and is appropriately localized in nucleoli to limit these processes. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
    Full-text · Article · Jun 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Show more