Interaction of the human T-lymphotropic virus type 1 Tax dimer with CREB and the viral 21-base-pair repeat

Abstract

Human T-lymphotropic virus type 1 Tax interacts specifically with the cellular transcription factor CREB and the viral 21-bp repeat element to form a Tax-CREB-DNA ternary complex which mediates activation of viral mRNA transcription. Analyses of Tax and Tax mutants indicate that, like CREB, Tax incorporates into the ternary complex as a dimer. The ability of Tax to form a dimer is necessary for its interaction with CREB and the 21-bp element. Analyses of several Tax mutants with amino acid substitutions spanning residues 123 to 204 indicate that intersubunit Tax dimerization correlates with its ability to assemble into the ternary complex and activate transcription. Tax also enhances the DNA binding activities of specific bZip domains in vitro. The ability of Tax to enhance DNA binding of bZip proteins can be explained in part by Tax dimerization. This activity alone is not sufficient for transactivation. A dual amino acid substitution mutant of Tax, M47 (L319R, L320S), completely abrogated for activation of the human T-lymphotropic virus type 1 long terminal repeat as a result of a defect in the transactivation domain, continues to stimulate binding of bZip proteins to DNA.

Molecular Interactions Involved in the Transactivation of the Human T-Cell Leukemia Virus Type 1 Promoter Mediated by Tax and CREB-2 (ATF-4)

“…It is noteworthy that for both proteins, Tax and CREB-2, the domains which have been reported to be involved in protein dimerization, the cysteine-rich and leucine-zipper subdomains, respectively, are necessary to form a stable complex. This observation suggests that dimerization of both proteins could be required for a specific interaction, as already suggested for Tax and CREB (39,76).…”

“…Tax-Tax dimer formation in yeast offers one simple explanation for these experimental results. Indeed, Tax functions optimally as a homodimer (76) and its cysteine-rich zinc finger domain is a necessary region for dimerization (39). In the case of the mutant Tax 308-353, the GAL4 DNA binding domain, which binds DNA as a dimer (16), is directly fused to the C-terminal domain of Tax and thus could compensate for the absence of the dimerization domain of Tax.…”

CREB − a real culprit in oncogenesis

“…Tax acts potently through viral CREs on the LTR, which are also bound by CREB. For activation of HTLV-I LTR and cellular CREB-regulated genes, dimeric Tax forms a ternary complex with dimeric CREB and the viral CRE [54][55][56][57][58][59]. In one model for Tax activation of CREB, Tax is thought to potentiate the dimerization and DNA binding of CREB and other bZIP transcription factors [60][61][62].…”

Seizing of T Cells by Human T-Cell Leukemia⧸Lymphoma Virus Type 1

“…Paca- Uccaralertkun et al, 1994;Tang et al, 1998). In vitro, Tax contacts this G-C-rich DNA-flanking sequence and acts as an anchor to recruit the cellular coactivator CREB to the transcription complex (Kimzey and Dynan, 1998;Lenzmeier et al, 1998), which in turn functions as a dimer and interacts directly through its basic domain-leucine zipper with the CRE-like sequence to activate transcription from the viral LTR (Brauweiler et al, 1995;Goren et al, 1995;Laurance et al, 1997;Paca-Uccaralertkun et al, 1994;Tie et al, 1996;Yin and Gaynor, 1996;Giam 1991, 1992). Several studies have suggested that these interactions stimulate the dimerization of bZIP-containing proteins and their DNA-binding activity (Armstrong et al, 1993;Baranger et al, 1995;Perini et al, 1995;Tie et al, 1996;Wagner and Green, 1993;Yin and Gaynor, 1996).…”