Human T-Cell Leukemia Virus Type 1 Tax Requires Direct Access to DNA for Recruitment of CREB Binding Protein to the Viral Promoter

Abstract

The virally encoded Tax protein is implicated in the various clinical manifestations associated with infection by human Tcell leukemia virus type 1 (HTLV-1), including an aggressive and fatal T-cell malignancy (for a review, see reference 18). The mechanism of lymphocyte transformation by Tax is not known, although it appears to be linked to the pleiotropic transcriptional deregulation properties associated with the Tax oncoprotein. Following T-cell infection, the retrovirus appears to establish and maintain a state of latency, with very low levels of viral gene expression (31, 34). The transition from latency to high-level viral RNA synthesis is initiated by an ill-defined signal which triggers Tax expression. Tax protein is transported into the nucleus, where it interacts with the three conserved 21-bp repeat elements located in the transcriptional control region of the virus, strongly activating viral gene expression (11,19,32,48,50,51).The interaction between Tax and the 21-bp repeats is facilitated by cellular transcription factors, which provide the primary recognition of these Tax-responsive elements (3,9,23,43,44). Centered within each 21-bp repeat is an off-consensus cyclic AMP (cAMP) response element, termed a viral CRE, which serves as the recognition element for members of the activating transcription factor/CRE binding protein (ATF/ CREB) family of cellular transcription factors. The CRE binding activity of these proteins is derived from their basic amino acid DNA binding domain and adjacent leucine zipper dimerization domain (bZIP domain). While several members of the ATF/CREB family bind to the CREs in the viral promoter, CREB appears to play the most prominent role in mediating Tax transactivation (1,2,4,9,12,17,24,36,56,(59)(60)(61)(62)(63).Although the precise molecular events which lead to Tax transactivation mediated through CREB are not well understood, several studies have established that Tax enters into a stable ternary complex with CREB and the viral CRE (12,26,46,54,61,63). In the absence of Tax, CREB forms an unstable complex with the viral CRE; however, in the presence of Tax, the dissociation rate of CREB is decreased (12). Studies with a variety of bZIP family members suggest that Tax interacts primarily, although not exclusively, with the bZIP region of CREB (1,7,12,17,49,56,60). This interaction may stabilize the ␣-helical structure of the parallel bZIP dimers, resulting in both enhanced DNA binding and dimerization of CREB (7,49,56). Together, these observations led to the suggestion that transactivation may occur as a consequence of Tax stabilization of CREB bound to the off-consensus viral CREs (12), leading to increased viral mRNA synthesis through the activation properties associated with CREB.This model for Tax transactivation was incomplete, because it did not address the role of CREB phosphorylation, which is necessary for CREB transcriptional activity (25). Recently, we and others (24, 36) have shown Tax directly interacts with the cellular coactivator CREB binding protei...

Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site

“…This would be mediated by the high a nity binding of Tax to CREB bound to the 21-bp enhancer. These results are consistent with previous reports (Giebler et al, 1997;Harrod et al, 1998;Lenzmeier et al, 1998) providing further direct evidence for e cient recruitment of CBP onto the enhancer.…”

“…Furthermore, Tax interacts with a transcriptional coactivator, CBP, which binds to the phosphorylated form of CREB (Chrivia et al, 1993). Through these binding capacities, Tax functions as a linker between CREB and CBP in a phosphorylation-independent manner on the viral enhancer, the 21-bp element (Giebler et al, 1997;Harrod et al, 1998;Kwok et al, 1996;Lenzmeier et al, 1998).…”

Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response

“…Furthermore, HTLV-1-infected cells display increased mutational events, an observation also noted for Tax-expressing cells (5,6,15). Although Tax has been shown to contact DNA (16), it is unlikely that this viral protein directly causes DNA damage as a result of physical contact but rather induces the accumulation of damage by impairing the cellular DNA damage repair response. A variety of possible mechanisms have been proposed to explain Tax-induced damage accumulation.…”

p300 and p300/cAMP-responsive Element-binding Protein Associated Factor Interact with Human T-cell Lymphotropic Virus Type-1 Tax in a Multi-histone Acetyltransferase/Activator-Enhancer Complex

“…Tax is known to directly interact with the basic domain leucine zipper (bZip) of CREB/ATF-1, which binds the core cyclic AMP-responsive element (CRE) in each 21-bp repeat (7,13,21,35). Recent data suggest that, upon binding to the basic domain of CREB bZip, Tax makes additional contacts with the G/C-rich sequences that flank the CRE; thus achieving the exquisite DNA sequence specificity of Tax-mediated LTR trans-activation (35)(36)(37)(38). Kwok et al (39) have shown that the co-activator, CREBbinding protein (CBP), and its homologue, p300, directly bind to HTLV-1 Tax.…”