{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:54:50Z","timestamp":1790006090048,"version":"4.0.1"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2004,5,20]],"date-time":"2004-05-20T00:00:00Z","timestamp":1085011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2004,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Trp53<\/jats:italic>\u2010deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in <jats:italic>Trp53<\/jats:italic>\u2010deficient mice. We therefore created mouse strains with different combinations of the <jats:italic>Trp53<\/jats:italic> and <jats:italic>iNOS<\/jats:italic> genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of <jats:italic>Trp53<\/jats:italic> status and its expression was enhanced in <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/\u2013<\/jats:italic><\/jats:sup> and <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mice compared to <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> mice. Homozygous disruption of <jats:italic>iNOS<\/jats:italic> decreased the incidence of thymic lymphomas by almost 40% (<jats:italic>p<\/jats:italic> = 0.087) and 90% (<jats:italic>p<\/jats:italic> &lt; 0.05) in <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> and <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/\u2013<\/jats:italic><\/jats:sup> mice, respectively, compared to the respective <jats:italic>iNOS<\/jats:italic> wild\u2010type mice but significantly (<jats:italic>p<\/jats:italic> &lt; 0.05) increased the development of nonthymic lymphomas in <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> and <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/\u2013<\/jats:italic><\/jats:sup> mice. Although <jats:italic>iNOS<\/jats:italic> gene disruption did not affect the phenotype of thymic lymphomas, absence of the <jats:italic>iNOS<\/jats:italic> gene shifted the spectrum of nonthymic lymphoma from the B\u2010cell to the T\u2010cell lineage. RT\u2010PCR analysis revealed enhanced expression of IL\u201010, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup><jats:italic>iNOS<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> and <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/\u2013<\/jats:italic><\/jats:sup><jats:italic>iNOS<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> but not <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup><jats:italic>iNOS<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> or <jats:italic>Trp53<\/jats:italic><jats:sup><jats:italic>+\/\u2013<\/jats:italic><\/jats:sup><jats:italic>iNOS<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>. These results suggest that iNOS could increase the development of thymic lymphomas in <jats:italic>Trp53<\/jats:italic>\u2010deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.20350","type":"journal-article","created":{"date-parts":[[2004,5,20]],"date-time":"2004-05-20T19:02:51Z","timestamp":1085079771000},"page":"819-828","source":"Crossref","is-referenced-by-count":15,"title":["Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in <i>Trp53<\/i>\u2010deficient mice lacking inducible nitric oxide synthase 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