The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.
Roman S, Pétré A, Thépot A, Hautefeuille A, Scoazec J-Y, Mion F, Hainaut P. Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol 293: G45-G53, 2007. doi:10.1152/ajpgi.00583.2006. p63 is a member of the p53 protein family that regulates differentiation and morphogenesis in epithelial tissues and is required for the formation of squamous epithelia. Barrett's mucosa is a glandular metaplasia of the squamous epithelium that develops in the lower esophagus in the context of chronic, gastroesophageal reflux and is considered as a precursor for adenocarcinoma. Normal or squamous cancer esophageal cells were exposed to deoxycholic acid (DCA, 50, 100, or 200 M) and chenodeoxycholic and taurochenodeoxycholic acid at pH 5. p63 and cyclooxygenase-2 (COX-2) expressions were studied by Western blot and RT-PCR. DCA exposure at pH 5 led to a spectacular decrease in the levels of all isoforms of the p63 proteins. This decrease was observed within minutes of exposure, with a synergistic effect between DCA and acid. Within the same time frame, levels of p63 mRNA were relatively unaffected, whereas levels of COX-2, a marker of stress responses often induced in Barrett's mucosa, were increased. Similar results were obtained with chenodeoxycholic acid but not its taurine conjugate at pH 5. Proteasome inhibition by lactacystin or MG-132 partially blocked the decrease in p63, suggesting a posttranslational degradation mechanism. These results show that combined exposure to bile salt and acid downregulates a critical regulator of squamous differentiation, providing a mechanism to explain the replacement of squamous epithelium by a glandular metaplasia upon exposure of the lower esophagus to gastric reflux.
TP63 gene is a member of TP53 tumor suppressor gene family that encodes several protein isoforms involved in the process of epithelial stratification and in epithelial-mesenchyme interactions. TP63 is amplified in a significant proportion of squamous cell carcinoma of the esophagus (ESCC), resulting in the hyper-expression of DNp63 as the major p63 isoform. To better understand the contribution of this high expression to tumorigenesis, we have analyzed the impact of intraepithelial p63 expression on the expression of cell adhesion complexes in normal esophagus and in ESCC cell lines. Cells expressing p63 showed an adhesion pattern characterized by lack of tight junctions and presence of adherens junctions. Cell differentiation was accompanied by a decrease in p63 and by a shift to adhesion patterns involving tight junctions. Silencing of p63 mRNA in ESCC cell lines resulted in a similar shift, characterized by increased expression of component of tight junctions, decreased cell-to-cell communication and downregulation of cell proliferation. These results indicate that DNp63 may contribute to esophageal squamous carcinogenesis by maintaining cell adhesion patterns compatible with cell proliferation.TP63 is a paralogue of TP53 that shares its general transcription factor architecture and DNA-binding properties toward response elements located in regulatory regions of multiple anti-proliferative, pro-apoptotic and pro-differentiation regulators. 1,2 Its expression pattern is complex, resulting in the synthesis of multiple isoforms that retain the central DNAbinding domain but differ by their N-and C-terminal domains. These isoforms are produced by alternative splicing (for the three C-terminal variants, identified as a, b and c) and by the use of an alternative promoter located in intron 3 (for the two N-terminal isoforms, identified as TA and DN, TA being the full-length form that contains the N-terminal transactivation domain). 2,3 In squamous cell carcinomas of the lung, oral cavity or esophagus, TP63 is amplified in about 20 to 25% of the cases, leading to overexpression of the p51 AIS protein, which has now been identified as one of the 6 protein isoforms of p63 corresponding to DNp63a. The pathological consequences of the deregulation of p63 expression appear to be complex. [4][5][6] Patturajan et al. 7 have reported that DNp63 induces b-catenin nuclear accumulation and signaling. In contrast, studies by Higashikawa et al. 8,9 have shown that DNp63a is involved in suppressing the invasive phenotype of human squamous cell carcinomas.Evidence from knock-out mice demonstrates that TP63 is an essential regulator of mesenchyme-epidermal interactions and of the morphogenesis of stratified epithelia 10,11 Among other developmental defects, mice lacking TP63 fail to form stratified epithelium of epidermis, oral cavity and esophagus. In TP63-null mice, the squamous esophageal epithelium is replaced by a columnar, poorly differentiated, ciliated epithelium. 12 In skin, there is evidence that the lack of stratification ...
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