{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:28:12Z","timestamp":1791250092904,"version":"4.1.0"},"reference-count":44,"publisher":"The Company of Biologists","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,6,1]]},"abstract":"<jats:p>p53 is the most frequently mutated tumour-suppressor gene in human cancers. Mutant p53 is thought to contribute to carcinogenesis by the acquisition of gain-of-function properties or through the exertion of dominant-negative (DN) effects over the remaining wild-type protein. However, the context in which the DN effects are observed is not well understood. We have therefore generated `knock-in' mouse embryonic stem (ES) cells to investigate the effects of expressing a commonly found hot-spot p53 mutant, R246S \u2013 the mouse equivalent of human R249S, which is associated with hepatocellular carcinomas. We demonstrate here that R246S mutant p53 exhibits DN effects with respect to target gene expression, cell survival and cell cycle arrest both in cells that are in the undifferentiated state and upon differentiation. The knock-in cells contain higher levels of p53 that localizes to the nucleus even in the absence of genotoxic stress and yet remains non-functional, reminiscent of mutant p53 found in human tumours. In a model based on carbon-tetrachloride-induced liver injury, these cells were consistently highly tumorigenic in vivo, similar to p53\u2013\/\u2013 cells and in contrast to both p53+\/+ and p53+\/\u2013 ES cells. These data therefore indicate that the DN effects of mutant p53 are evident in the stem-cell context, in which its expression is relatively high compared with terminally differentiated cells.<\/jats:p>","DOI":"10.1242\/jcs.022822","type":"journal-article","created":{"date-parts":[[2008,5,14]],"date-time":"2008-05-14T00:34:51Z","timestamp":1210725291000},"page":"1899-1906","source":"Crossref","is-referenced-by-count":30,"title":["The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo"],"prefix":"10.1242","volume":"121","author":[{"given":"Ming Kei","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanaga","family":"Sabapathy","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore"},{"name":"Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042520112807400_REF1","doi-asserted-by":"crossref","unstructured":"Aurelio, O. N., Kong, X. T., Gupta, S. and Stanbridge, E. J. (2000). p53 mutants have selective dominant-negative effects on apoptosis but not growth arrest in human cancer cell lines. Mol. Cell. Biol.20, 770-778.","DOI":"10.1128\/MCB.20.3.770-778.2000"},{"key":"2021042520112807400_REF2","doi-asserted-by":"crossref","unstructured":"Brazel, C. Y., Romanko, M. J., Rothstein, R. P. and Levison, S. W. (2003). Roles of the mammalian subventricular zone in brain development. Prog. Neurobiol.69, 49-69.","DOI":"10.1016\/S0301-0082(03)00002-9"},{"key":"2021042520112807400_REF3","doi-asserted-by":"crossref","unstructured":"Brooks, D. G., James, R. M., Patek, C. E., Williamson, J. and Arends, M. J. (2001). Mutant K-ras enhances apoptosis in embryonic stem cells in combination with DNA damage and is associated with increased levels of p19(ARF). Oncogene20, 2144-2152.","DOI":"10.1038\/sj.onc.1204309"},{"key":"2021042520112807400_REF4","unstructured":"Chan, W. M., Siu, W. Y., Lau, A. and Poon, R. Y. (2004). How many mutant p53 molecules are needed to inactivate a tetramer? Mol. Cell. Biol.24, 3536-3551."},{"key":"2021042520112807400_REF5","doi-asserted-by":"crossref","unstructured":"Chao, C., Saito, S., Anderson, C. W., Appella, E. and Xu, Y. (2000). Phosphorylation of murine p53 at ser-18 regulates the p53 responses to DNA damage. Proc. Natl. Acad. Sci. USA97, 11936-11941.","DOI":"10.1073\/pnas.220252297"},{"key":"2021042520112807400_REF6","doi-asserted-by":"crossref","unstructured":"Clarke, A. R., Purdie, C. A., Harrison, D. J., Morris, R. G., Bird, C. C., Hooper, M. L. and Wyllie, A. H. (1993). Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature362, 849-852.","DOI":"10.1038\/362849a0"},{"key":"2021042520112807400_REF7","unstructured":"Davis, P., Bazar, K., Huper, G., Lozano, G., Marks, J. and Iglehart, J. D. (1996). Dominance of wild-type p53-mediated transcriptional activation in breast epithelial cells. Oncogene13, 1315-1322."},{"key":"2021042520112807400_REF8","doi-asserted-by":"crossref","unstructured":"de Vries, A., Flores, E. R., Miranda, B., Hsieh, H. M., van Oostrom, C. T., Sage, J. and Jacks, T. (2002). Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc. Natl. Acad. Sci. USA99, 2948-2953.","DOI":"10.1073\/pnas.052713099"},{"key":"2021042520112807400_REF9","doi-asserted-by":"crossref","unstructured":"Fenoglio-Preiser, C. M., Wang, J., Stemmermann, G. N. and Noffsinger, A. (2003). TP53 and gastric carcinoma: a review. Hum. Mutat.21, 258-270.","DOI":"10.1002\/humu.10180"},{"key":"2021042520112807400_REF10","doi-asserted-by":"crossref","unstructured":"Forslund, A., Kressner, U., Lonnroth, C., Andersson, M., Lindmark, G. and Lundholm, K. (2002). P53 mutations in colorectal cancer assessed in both genomic DNA and cDNA as compared to the presence of p53 LOH. Int. J. Oncol.21, 409-415.","DOI":"10.3892\/ijo.21.2.409"},{"key":"2021042520112807400_REF11","doi-asserted-by":"crossref","unstructured":"Ghebranious, N. and Sell, S. (1998). Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice. Hepatology27, 383-391.","DOI":"10.1002\/hep.510270211"},{"key":"2021042520112807400_REF12","doi-asserted-by":"crossref","unstructured":"Ghebranious, N., Knoll, B. J., Wu, H., Lozano, G. and Sell, S. (1995). Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. Mol. Carcinog.13, 104-111.","DOI":"10.1002\/mc.2940130207"},{"key":"2021042520112807400_REF13","doi-asserted-by":"crossref","unstructured":"Harvey, M., Vogel, H., Morris, D., Bradley, A., Bernstein, A. and Donehower, L. A. (1995). A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53-deficient mice. Nat. 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Cancer Res.53, 368-372."},{"key":"2021042520112807400_REF26","unstructured":"Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M. and Hirohashi, S. (1992). p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res.52, 6358-6364."},{"key":"2021042520112807400_REF27","doi-asserted-by":"crossref","unstructured":"Oda, T., Tsuda, H., Sakamoto, M. and Hirohashi, S. (1994). Different mutations of the p53 gene in nodule-in-nodule hepatocellular carcinoma as a evidence for multistage progression. Cancer Lett.83, 197-200.","DOI":"10.1016\/0304-3835(94)90319-0"},{"key":"2021042520112807400_REF28","doi-asserted-by":"crossref","unstructured":"Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D. and Jacks, T. (2004). Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell119, 847-860.","DOI":"10.1016\/j.cell.2004.11.004"},{"key":"2021042520112807400_REF29","unstructured":"Olivier, M., Hussain, S. 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Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. 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