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      p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.

      Molecular Cell

      Amino Acid Sequence, Animals, Chromosome Mapping, Chromosomes, Human, Pair 3, Crosses, Genetic, DNA-Binding Proteins, Female, Genes, Tumor Suppressor, Genes, p53, Humans, In Situ Hybridization, Fluorescence, Introns, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Muridae, Phosphoproteins, chemistry, genetics, Polymorphism, Genetic, Protein Isoforms, Sequence Alignment, Sequence Homology, Amino Acid, Trans-Activators, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins

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          Abstract

          We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.

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          Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.

          Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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            p53 mutations in human cancers

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              Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.

              p21CIP1/WAF1 is a CDK inhibitor regulated by the tumor suppressor p53 and is hypothesized to mediate G1 arrest. p53 has been suggested to derive anti-oncogenic properties from this relationship. To test these notions, we created mice lacking p21CIP1/WAF1. They develop normally and (unlike p53-/- mice) have not developed spontaneous malignancies during 7 months of observation. Nonetheless, p21-/- embryonic fibroblasts are significantly deficient in their ability to arrest in G1 in response to DNA damage and nucleotide pool perturbation. p21-/- cells also exhibit a significant growth alteration in vitro, achieving a saturation density as high as that observed in p53-/- cells. In contrast, other aspects of p53 function, such as thymocytic apoptosis and the mitotic spindle checkpoint, appear normal. These results establish the role of p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and the anti-oncogenic effects of p53 are more complex.
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                Author and article information

                Journal
                9774969
                10.1016/S1097-2765(00)80275-0

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