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...

EIAF is a newly isolated ETS-family gene that is located on 17q21 and codes for the adenovirus EIA enhancer-binding protein. In our chromosome analysis of 18 of the Ewing family of tumors and undifferentiated sarcomas, we found t(17;22)(q12;q12) in an MIC2 antigen-positive undifferentiated sarcoma of infancy. On Southern blot analysis, EWS and EIAF cDNA probes hybridized to the same rearranged band, indicating that an EWS-EIAF fusion gene was formed in the tumor. Further Southern blot analysis using four EIAF cDNA probes of different sizes showed that the breakpoint lies in the region upstream to the ETS domain of the EIAF gene. EIAF may be the fourth ETS-family gene to be identified forming a fusion gene with EWS. We assume that the RNA binding domain of EWS may have been replaced by the DNA binding domain of EIAF in the EWS-EIAF fusion protein as in other fusion proteins previously characterized in Ewing sarcoma and other types of sarcomas.

Two p53‐related genes, p73 and p51, were recently identified as structural homologues of the p53 tumor suppressor gene, suggesting that the roles of these two genes may be similar to those of p53, including growth suppression and induction of apoptosis. Here we show that introduction of p73 or p51 cDNAs into cultured human cancer cells suppressed colony formation in the presence of G418. We then examined the ability of various isoforms of p73 and p51 to activate transcription of a reporter gene. This assay showed that p73 β and p51A activated transcription through a consensus p53 binding sequence, while p73 α and p51B isoforms minimally transactivated the p53 reporter gene. To characterize further the biological functions of the p53‐related genes, we constructed recombinant adenoviruses containing the p73 and p51 cDNAs. Ad‐p73 β and Ad‐p51A induced endogenous p21 gene expression more effectively than Ad‐p73 β and Ad‐p51B, respectively. To evaluate the mode of cell death induced by p53‐related genes, Ad‐p73 and Ad‐p51 were used to infect human cancer cells. Infection of Ad‐p73 β, Ad‐p51A or Ad‐p51B resulted in DNA fragmentation in a subset of cancer cell lines more efficiently than did infection of Ad‐p53. We then examined the combined effect of each p53‐related gene and the E1A oncogene in the induction of apoptosis. The E1A oncogene cooperated with p51 as well as p53 to induce apoptosis, while p73 resulted in a weak induction of apoptosis by E1A. Overall, apoptosis induction by p51B and p73 α isoforms may be due to mechanisms other than transcriptional activation of p53‐target genes. Our results suggest that p53‐related genes are both similar to and different from p53 in their pathways leading to growth suppression.

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