Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). The HTLV-1 Tax protein has been strongly linked to oncogenesis and is considered to be the transforming protein of this virus. A Tax transgenic mouse model was utilized to study the contribution of p53 inactivation to Tax-mediated tumorigenesis. These mice develop primary, peripheral tumors consisting of large granular lymphocytic (LGL) cells, which also infiltrate the lymph nodes, bone marrow, spleen, liver, and lungs. Primary Tax-induced tumors and tumor-derived cell lines exhibited functional inactivation of the p53 apoptotic pathway; such tumors and tumor cell lines were resistant to an apoptosis-inducing stimulus. In contrast, p53 mutations in tumors were found to be associated with secondary organ infiltration. Three of four identified mutations inhibited transactivation and apoptosis induction activities in vitro. Furthermore, experiments which involved mating Tax transgenic mice with p53-deficient mice demonstrated minimal acceleration in initial tumor formation, but significantly accelerated disease progression and death in mice heterozygous for p53. These studies suggest that functional inactivation of p53 by HTLV-1 Tax, whether by mutation or another mechanism, is not critical for initial tumor formation, but contributes to late-stage tumor progression.
Portis
T
T
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Grossman
W J
WJ
Harding
J C
JC
Hess
J L
JL
Ratner
L
L
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D018450:Disease Progression; D016356:Gene Products, tax / Q000502:physiology*; D016158:Genes, p53; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016356:Gene Products, tax; D016159:Tumor Suppressor Protein p53