Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers

Sanofi Recherche, Labege, France.
Cell (Impact Factor: 32.24). 09/1997; 90(4):809-19. DOI: 10.1016/S0092-8674(00)80540-1
Source: PubMed


We describe a gene encoding p73, a protein that shares considerable homology with the tumor suppressor p53. p73 maps to 1p36, a region frequently deleted in neuroblastoma and other tumors and thought to contain multiple tumor suppressor genes. Our analysis of neuroblastoma cell lines with 1p and p73 loss of heterozygosity failed to detect coding sequence mutations in remaining p73 alleles. However, the demonstration that p73 is monoallelically expressed supports the notion that it is a candidate gene in neuroblastoma. p73 also has the potential to activate p53 target genes and to interact with p53. We propose that the disregulation of p73 contributes to tumorigenesis and that p53-related proteins operate in a network of developmental and cell cycle controls.

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    • "The polymorphism c.325À4742T>G (rs17506395) of the TP63 gene was associated with infertility [6]. In the TP73 gene, two closely linked polymorphisms at positions 4c.À30G>A and 14c.À20C>T (rs2273953, rs1801173), located before the start codon, can form a hairpin structure with the potential to alter the genetic expression [15]. The MDM2 gene, the major negative regulator of the p53 family proteins, has an important polymorphism (c.14+309T>G, SNP309, rs2279744) which has been associated with infertility [16]. "
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    ABSTRACT: Objective: Recent studies have investigated the role of the p53 gene family in reproductive processes. Each member of the gene family acts through different mechanisms: p53 is involved in genomic stability and regulation of blastocyst implantation; p63 acts as a regulator of the quality and maturation of oocytes; and p73 controls the meiotic spindle. Polymorphisms in the genes of the p53 family have been associated with female infertility. One polymorphism in MDM2, the main regulator of the p53 family, has also been associated with this condition. Although polymorphisms in the TP53 gene have been related to recurrent pregnancy loss (RPL), there have been no studies associating polymorphisms in p63 and p73 with RPL. Therefore, the aim of this study was to evaluate the role of polymorphisms in the TP63 (rs17506395), TP73 (rs2273953, rs1801173), and MDM2 (SNP309, rs2279744) genes as risk factors for RPL. Study design: A case-control study was conducted in 153 women with RPL and 143 fertile women with at least two living children and no history of pregnancy loss. Molecular analysis was performed by TaqMan Allelic Discrimination assay. The statistical analysis was performed using SPSS software version 20.0 and the chi-square test, Student's t-test, Mann-Whitney test and logistic regression to compare the evaluated characteristics between both groups and RPL outcome. Results: The allelic and genotypic frequencies did not differ between the groups when analyzed separately, however, the interaction between the TP63 TT and MDM2 TT genotypes was shown to increase the risk of RPL (OR=2.19, CI 95%: 1.28-3.75, p=0.004), even when adjusted for alcohol consumption, smoking, number of pregnancies and ethnicity (OR=1.97, CI 95%: 1.27-3.58, p=0.025). Conclusions: Our results suggest that genes from the p53 family proteins, evaluated here, have an influence on the risk of RPL.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2014; 182C:7-10. DOI:10.1016/j.ejogrb.2014.07.044 · 1.70 Impact Factor
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    • "The TP63 (MIM * 603273) and TP73 genes express, by alternative promoter usage and splicing, multiple transactivation competent (TA) and truncated N-terminal (N) variants [Kaghad et al., 1997; Yang et al., 1998]. Although evolutionary conservation is higher for the DBD, it is still apparent in the amino-terminal transactivation domain and in the carboxy-terminal tetramerization domain [Dotsch et al., 2010]. "
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    ABSTRACT: Loss-of-function, partial-function, altered-function, dominant-negative, temperature sensitive; interfering; contact; structural; unfolded; misfolded; dimeric; monomeric; non-cooperative; unstable; supertrans; superstable; intragenic suppressor. TP53 mutants: they are many, more than 2000 in fact, and they can be very diverse. Sporadic; germline; gain-of-function; oncogenic; rebel-angel; yin and yang; prion-like; metastasis-inducer; mediator of chemo-resistance; modifier of stemness. TP53 mutants can impact on important cancer clinical variables, in multiple, often subtle ways, as revealed by cell-based assays as well as animal models. Here we review studies investigating TP53 mutants for their effect on sequence-specific transactivation function, and especially recent findings on how TP53 mutants can exhibit gain-of-function properties. We also review reports on TP53 mutants' impact on cancer cell transcriptomes and studies with Li-Fraumeni patients trying to classify and predict phenotypes in relation to experimentally determined transcription fingerprints. Finally, we provide an example of the complexity of correlating TP53 mutant functionality to clinical variables in sporadic cancer patients. Conflicting results and limitations of experimental approaches notwithstanding, the study of TP53 mutants has provided a rich body of knowledge, mostly available in the public domain and accessible through databases, that is beginning to impact on cancer intervention strategies. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2014; 35(6). DOI:10.1002/humu.22514 · 5.14 Impact Factor
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    • "It has been shown how mutp53 reaches target gene promoters through the interaction with sequence-specific transcription factors, such as NF-Y, E2F1, NF-kB and the Vitamin D receptor [6] [7] [8] [9]. In such aberrant cells, the p53 activity could be, at least in part, vicariated by two members of its family, p63 and p73, that share high structural and functional homology with p53 [10] [11] [12] [13]. In fact, both p63 and p73 are activated by the same signaling pathways that lead to the p53 activation and stimulate the transcription of p53 responsive genes controlling cell proliferation , differentiation and death [14]. "
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    ABSTRACT: TP53 tumor suppressor gene is mutated in more than 50% of human tumours. Mutated p53 proteins could sequestrate and inactivate p73 reducing the apoptotic and anti-proliferative effects of the transcription factor, and yelding cancer cells more aggressive and chemoresistant. The possibility to use drugs to prevent the mutant p53/p73 complex formation preserving the p73 function, calls for deeper insight into the molecular and biochemical mechanisms of mutant p53/p73 protein interaction. the kinetics of the mutant p53R175H/p73 complex was investigated with innovative and complementary techniques, operating in real time, in near physiological conditions and without any labeling. Specifically, Atomic Force Spectroscopy and Surface Plasmon Resonance working at single-molecule level and in bulk condition, respectively, were used. the two techniques revealed that a stable complex is formed between mutant p53R175H and p73 proteins; the complex being characterized by a high interaction force and a dissociation equilibrium constant in the order of 10(-7)M, as expected for specific interactions. No binding was instead observed between p73 and wild type p53. mutant p53R175H protein, unlike wild type p53, can form a stable complex with p73. The mutant p53R175H/p73 protein complex could be a target for innovative pharmaceutical drugs that, by dissociating it or preventing biomolecules interaction thus preserving the p73 function, could enhance the response of cancerous cells carrying mutant p53R175H protein to common chemotherapeutic agents. General significance the kinetic information obtained in vitro may help to design specific pharmaceutical drugs directed against cancerous cells carrying mutant p53 proteins.
    Biochimica et Biophysica Acta (BBA) - General Subjects 06/2014; 1840:1958-1964. DOI:10.1016/j.bbagen.2014.02.014 · 4.38 Impact Factor
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