Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model

T. Portis, W. J. Grossman, J. C. Harding, Jay Hess, L. Ratner

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2185-2193
Number of pages9
JournalJournal of Virology
Volume75
Issue number5
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Deltaretrovirus
taxes
Transgenic Mice
inactivation
animal models
genetically modified organisms
neoplasms
Neoplasms
Tumor Cell Line
mice
Mutation
mutation
Carcinogenesis
carcinogenesis
tax Gene Products
Apoptosis
apoptosis
cell lines
Adult T Cell Leukemia Lymphoma
transcriptional activation

ASJC Scopus subject areas

  • Immunology

Cite this

Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model. / Portis, T.; Grossman, W. J.; Harding, J. C.; Hess, Jay; Ratner, L.

In: Journal of Virology, Vol. 75, No. 5, 2001, p. 2185-2193.

Research output: Contribution to journalArticle

Portis, T. ; Grossman, W. J. ; Harding, J. C. ; Hess, Jay ; Ratner, L. / Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model. In: Journal of Virology. 2001 ; Vol. 75, No. 5. pp. 2185-2193.
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