| First Author | Ohsugi T | Year | 2013 |
| Journal | Carcinogenesis | Volume | 34 |
| Issue | 9 | Pages | 2129-36 |
| PubMed ID | 23633516 | Mgi Jnum | J:200097 |
| Mgi Id | MGI:5506983 | Doi | 10.1093/carcin/bgt144 |
| Citation | Ohsugi T, et al. (2013) p53 dysfunction precedes the activation of nuclear factor-kappaB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein. Carcinogenesis 34(9):2129-36 |
| abstractText | 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-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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-kappaB activation with the components of p50 and RelB. An NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-kappaB 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-kappaB activation in the early stage, might be the first stage in the onset of ATLL. NF-kappaB activity is involved in the later stages of ATLL onset. |
