Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53-deficient mice lacking inducible nitric oxide synthase gene

Masayuki Tatemichi, Hiroshi Tazawa, Mitsuharu Masuda, Mohammad Saleem, Sayori Wada, Lawrence A. Donehower, Hiroko Ohgaki, Hiroshi Ohshima

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Trp53-deficient 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 Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53 +/- and Trp53-/- mice compared to Trp53+/+ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p = 0.087) and 90% (p <0.05) in Trp53-/- and Trp53+/- mice, respectively, compared to the respective iNOS wild-type mice but significantly (p <0.05) increased the development of nonthymic lymphomas in Trp53-/- and Trp53+/- mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53 -/-iNOS-/- and Trp53+/-iNOS-/- but not Trp53-/-iNOS+/+ or Trp53+/-iNOS +/+. These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient 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.

Original languageEnglish
Pages (from-to)819-828
Number of pages10
JournalInternational Journal of Cancer
Volume111
Issue number6
DOIs
Publication statusPublished - Oct 10 2004
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type II
Lymphoma
Genes
Thymus Gland
B-Cell Lymphoma
Cell Lineage
Interleukin-10
Spleen
Western Blotting
Cytokines
T-Lymphocytes
Phenotype
Polymerase Chain Reaction
Incidence

Keywords

  • Bilateral effect
  • Double mutant mouse
  • INOS
  • Lymphomagenesis
  • Trp53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53-deficient mice lacking inducible nitric oxide synthase gene. / Tatemichi, Masayuki; Tazawa, Hiroshi; Masuda, Mitsuharu; Saleem, Mohammad; Wada, Sayori; Donehower, Lawrence A.; Ohgaki, Hiroko; Ohshima, Hiroshi.

In: International Journal of Cancer, Vol. 111, No. 6, 10.10.2004, p. 819-828.

Research output: Contribution to journalArticle

Tatemichi, Masayuki ; Tazawa, Hiroshi ; Masuda, Mitsuharu ; Saleem, Mohammad ; Wada, Sayori ; Donehower, Lawrence A. ; Ohgaki, Hiroko ; Ohshima, Hiroshi. / Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53-deficient mice lacking inducible nitric oxide synthase gene. In: International Journal of Cancer. 2004 ; Vol. 111, No. 6. pp. 819-828.
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abstract = "Trp53-deficient 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 Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53 +/- and Trp53-/- mice compared to Trp53+/+ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40{\%} (p = 0.087) and 90{\%} (p <0.05) in Trp53-/- and Trp53+/- mice, respectively, compared to the respective iNOS wild-type mice but significantly (p <0.05) increased the development of nonthymic lymphomas in Trp53-/- and Trp53+/- mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53 -/-iNOS-/- and Trp53+/-iNOS-/- but not Trp53-/-iNOS+/+ or Trp53+/-iNOS +/+. These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient 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.",
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AU - Saleem, Mohammad

AU - Wada, Sayori

AU - Donehower, Lawrence A.

AU - Ohgaki, Hiroko

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