title: Exon 1 disruption alters tissue-specific expression of mouse p53 and results in selective development of B cell lymphomas.
abstract: p53 is a tumor suppressor gene mutated in >50% of human cancers, while p53 deficiency in mice results in cancers and accelerated mortality. Thymic T cell lymphoma is the most common malignancy in p53-deficient mice, making it difficult to study the role of p53 in other malignancies. To overcome this limitation, we attempted to generate mice with a reversible p53 knockout (p53(rev/rev)) by inserting a floxed transcriptional stop into the first exon of p53, anticipating that this would allow tissue-specific Cre-mediated expression of p53. Contrary to expectations, functional p53 protein was expressed in the thymus and multiple other tissues of p53(rev/rev) mice in the absence of Cre, whereas B cells expressed p53 protein only in the presence of B cell-specific CD19-Cre. In the absence of Cre, 76% of p53(rev/rev) mice developed splenic marginal zone B cell lymphomas, indicating sensitivity of this B cell subset to transformation caused by p53 deficiency. 5'-RACE identified p53 mRNA transcribed from a novel start site utilized in thymocytes but not normal B cells or B cell lymphomas from p53(rev/rev) mice. The p53(rev/rev) mouse thus demonstrates an effect of p53 deficiency in development of splenic marginal zone lymphomas and provides a model for study of p53-deficient human B cell lymphomas.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. chiangj@mail.nih.gov
authors.forename: Y Jeffrey
authors.initials: YJ
authors.lastname: Chiang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Difilippantonio
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hodes
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D016159:Tumor Suppressor Protein p53