Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
FUNCTIONAL ANALYSES OF THE TYPE I HUMAN T-CELL LEUKEMIA VIRUS TAX GENE PRODUCT
Diss Abstr Int [B]; 52(8):4040 1992. Unique Identifier : AIDSLINE ICDB/92682237 Smith MR; Duke Univ.
Abstract:
The type I human T-cell leukemia virus (HTLV-I) is distinguished from most other animal retroviruses by the complexity of its genome. In addition to the gag, pol, and env gene products encoded by all replication competent retroviruses, HTLV-I encodes two trans-regulatory proteins termed Tax and Rex. Tax trans-activator protein activates transcription of both viral and cellular genes. Tax also has the capacity to transform cells and appears to participate directly in viral pathogenesis. The present studies investigate potential mechanisms by which Tax mediates these diverse biological effects. Tax activates transcription of the HTLV-I long terminal repeat (LTR) and certain cellular and heterologous viral promoters. Tax does not specifically bind to DNA but, rather, activates transcription in a more indirect manner. Tax trans-activation of the HTLV-I LTR and c-fos proto-oncogene appears to involve members of the cAMP response element binding (CREB) and activating transcription factor (ATF) family of DNA binding proteins. In contrast, Tax trans-activation of the interleukin-2 receptor alpha chain gene and LTR of the type I human immunodeficiency virus involves the induced nuclear expression of members of the NF-kappaB/Rel transcription factor family. The identification of tax gene mutants that functionally segregate Tax activation of CREB/ATF-dependent and kappaB-dependent promoters suggests that this viral protein activates these cellular transcription factor pathways by at least two different mechanisms. Tax is expressed predominantly in the nuclei of cells. Subcellular localization of mutant and chimeric Tax proteins revealed that the amino terminus of Tax is both necessary for nuclear accumulation of Tax and sufficient to retarget a large cytoplasmic protein to the nucleus. This functional Tax nuclear localization signal (NLS) is distinguished from most previously described NLSs by its large size and low net positive charge, suggesting that this domain may represent a novel type of NLS. Tax-mediated cellular transformation likely results from activation of genes involved in cell growth. The potential role of the CREB/ATF and NF-kappa B/Rel transcription factor pathways in Tax-mediated cellular transformation was investigated by examining the oncogenic potential of rat fibroblasts stably expressing Tax mutants that functionally segregate these two pathways of trans-activation. Rat fibroblasts expressing either the wild type Tax or a Tax mutant selectively deficient in the ability to induce NF-kappa B/Rel demonstrated marked changes in morphology and growth characteristics including the ability to form tumors in vivo. In contrast, rat fibroblasts stably expressing a Tax mutant selectively deficient in the ability to activate CREB/ATF demonstrated no detectable changes in morphology or growth characteristics. These results suggest that Tax activation of CREB/ATF is required for transformation of rat fibroblasts and raises the possibility that Tax activation of this cellular transcription factor family plays an important role in HTLV-I-induced malignancy. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD92-04363).
Keywords: Cell Transformation, Neoplastic/GENETICS Fibroblasts/PHYSIOLOGY Gene Products, rex/PHYSIOLOGY Gene Products, tax/*PHYSIOLOGY NF-kappa B/GENETICS Proto-Oncogene Proteins c-fos/GENETICS Signal Transduction/GENETICS Transcription Factors/GENETICS Transcription, Genetic THESIS 921030
M92A1038
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
