The p53 tumor suppressor is a transcription factor that regulates cell growth and death in response to environmental stimuli such as DNA damage. p63/p51 and p73 were recently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. Mice that lack p53 are developmentally normal, while p63 and p73 appear to play critical roles in normal development. To determine how p63 and p73 are involved in normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not by p53. We found that the Jagged1 (JAG1) and Jagged2 (JAG2) genes, encoding ligands for the Notch receptors, are up-regulated by p63 and p73. Furthermore, we identified a p63-binding site in the second intron of the JAG1 gene, which can directly interact with the p63 protein in vivo, as assessed by a chromatin immunoprecipitation assay. A heterologous reporter assay revealed that this p63-binding site is a functional response element and is specific for p63. We also found a target of Notch signaling, HES-1 was up-regulated in Jurkat cells, in which Notch1 is highly expressed, when co-cultured with p63-transfected cells, suggesting that p63 can trigger the Notch signal pathway in neighboring cells. Our findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development.The involvement of the p53 tumor suppressor gene in cell growth and death is mediated by the transactivation of p53-target genes in response to environmental stimuli such as DNA damage (1-3). p63/p51 and p73 were recently identified as members of the p53 gene family and encode proteins that share considerable structural homology with p53 (4 -6). p63 and p73 can bind to the p53-responsive elements and up-regulate some p53-target genes, which suggest that the p53 family members have a potential for functional overlap with p53 itself (7-12). However, in contrast to p53, p63 and p73 are rarely mutated in human cancers (13)(14)(15).Different phenotypes between p63-or p73-deficient and p53-deficient mice were also reported (16 -19). In contrast to p53-deficient mice, mice lacking the p73 genes show no increased susceptibility to spontaneous tumorigenesis. p73-deficient mice have neurological, pheromonal and inflammatory defects. p63-deficient mice have major defects in their limbs and craniofacial development, as well as a striking absence of stratified epithelia, suggesting that p63 is required for limb and epidermal morphogenesis. In humans, Li-Fraumeni syndrome patients have inherited mutations of the p53 gene and develop normally, but are predisposed to cancer (20), while heterozygous germline mutations in the p63 gene are the cause of ectrodactyly, ectodermal dysplasia, and facial clefts syndrome (21). These studies demonstrate a marked divergence in the developmental roles of p63 and p73 and further distinguished these p53 family genes from p53. Despite these revel...

p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro)

The TP53 tumor suppressor gene regulates a number of genes that are involved in cell-cycle inhibition, apoptosis, and maintaining genetic stability. Recently, two genes that have a role in immunosurveillance were identified as downstream targets of TP53. These genes, TAP1 and fractalkine, may contribute to suppress tumor growth through host immunosurveillance. It has been reported that the mouse secreted phosphoprotein osteopontin (Opn) is one of the key cytokines for type 1 immune responses mediated by macrophages. It also was reported that Opn may play a role in suppressing tumor growth in vivo. Here we identified Opn as a Tp53-target gene using mRNA differential display analysis of embryonic fibroblasts from Tp53-deficient mice. Furthermore, we found that Opn expression was upregulated by DNA damage-induced Tp53 activity and by adenovirus-mediated transfer of the human TP53 gene. In addition, a luciferase assay showed that the Opn gene has a functional Tp53-responsive element in its promoter region, and a chromatin immunoprecipitation assay confirmed interaction between the Opn promoter and Tp53 protein in vivo. These results suggest that OPN is a direct transcriptional target of TP53. The TP53-directed regulation of OPN expression suggests a novel model of TP53 participation in immunosurveillance, involving interaction with the host immune system to prevent damaged cells from undergoing malignant transformation.

Previous studies reported that mutation of the adenomatous polyposis coli (APC) gene was not observed in the majority of gastric cancers. To evaluate the role of the APC/β-catenin/Tcf pathway, we analyzed mutations in the β-catenin gene and the accumulation of β-catenin protein in gastric carcinomas. An interstitial deletion spanning exon 3 of the β-catenin gene was observed in 1 of 13 gastric cancer cell lines. No missense mutation was found in these 13 cell lines. Nuclear and/or cytoplasmic localization of β-catenin was observed in 16 of 70 primary gastric carcinomas by immunohistochemistry, while we found no mutations in exon 3 in 35 carcinoma tissues available for PCR amplification. Our findings suggest that somatic mutations of the β-catenin gene are rare in human gastric carcinomas and that accumulation of normal β-catenin protein in a subset of gastric cancers may be due to other mechanisms of its activation.