title: p53 dysfunction precedes the activation of nuclear factor-κB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein.
abstract: Transgenic (Tg) mice expressing Tax, a human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, develop mature T-cell leukemia/lymphoma. The leukemic cells in Tg mice expressing Tax show p53 dysfunction and nuclear factor-κB (NF-κB) activation, similar to that seen in adult T-cell leukemia/lymphoma (ATLL) cells from patients infected with HTLV-1. However, it is unclear when these effects occur in HTLV-1 carriers during the development of ATLL. Here, we examined p53 function and NF-κB activity before the onset of leukemia in Tax-expressing Tg (Tax-Tg) mice between 4 and 25 months of age. At 4-10 months of age, 71% of mice showed p53 inactivation, without evidence for NF-κB activation, even though tax expression was consistent from 4 to 25 months of age. The decline in p53 function resulted from decreased p53 accumulation after DNA damage. From 11 months of age onward, 75% of mice showed p53 dysfunction and 37.5% showed constitutive NF-κB activation with the components of p50 and RelB. An NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-κB activity (i.e. p50/RelB) but did not restore p53 function. In vivo, treatment with DHMEQ until 24 months of age prevented the onset of T-cell leukemia in Tax-Tg mice. These results suggest that the Tax-induced decline in p53 function, which is independent of NF-κB activation in the early stage, might be the first stage in the onset of ATLL. NF-κB activity is involved in the later stages of ATLL onset.
authors: Division of Microbiology and Genetics, Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
authors: Takeo
authors: T
authors: Ohsugi
authors: Takaomi
authors: T
authors: Ishida
authors: Tatsuya
authors: T
authors: Shimasaki
authors: Seiji
authors: S
authors: Okada
authors: Kazuo
authors: K
authors: Umezawa
mesh_terms: D000328:Adult; D000818:Animals; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C514970:tax protein, Human T-lymphotrophic virus 1; D000072000:NF-KappaB Inhibitor alpha