Abstract
The human T-cell lymphotropic virus, type (HTLV)-1 trans-activator, Tax, coordinates with cAMP-responsive element-binding protein (CREB) and the transcriptional co-activators p300/CBP on three 21-base pair repeat elements in the proviral long terminal repeat (LTR) to promote viral mRNA transcription. Recruitment of p300/CBP to the activator-enhancer complex, however, is insufficient to support Tax-dependent LTR trans-activation. Here, we report that the p300/CBP-associated factor (P/CAF) is a critical and integral component of the functional HTLV-1 activator-enhancer complex. The HTLV-1 Tax protein directly binds P/CAF in vitro and co-immunoprecipitates with this co-activator in vivo. The Tax mutants (K88A and V89A) defective for p300/CBP-binding and LTR trans-activation, retained their abilities to interact with P/CAF. The M47 mutant (L319R, L320S) protein, which has previously been shown to interact with p300/CBP, by contrast, failed to form complexes with P/CAF and is impaired in LTR trans-activation. Furthermore, LTR trans-activation by Tax is competitively inhibited by the adenoviral E1A 12S gene product, which displaces P/CAF from p300/CBP and inhibits the histone acetyltransferase activities of both P/CAF and p300/CBP. This inhibition is partially reversed by exogenously added P/CAF. These results imply that simultaneous recruitment of two distinct co-activators (p300/CBP and P/CAF) by Tax is essential for the assembly of a trans-activation competent, nucleoprotein complex.
Highlights
The human T-cell lymphotropic virus, type-1 (HTLV-1),1 is the etiological agent of adult T-cell leukemia/lymphoma and a neurodegenerative disorder, known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP 1– 4)
HTLV-1 LTR trans-activation requires the assembly of the 40-kDa trans-activator Tax and CREB/ATF-1 transcription factors on three, 21-bp repeat enhancers located in the U3 region (22, 30 –34)
E1A 12S Inhibition of Tax-dependent LTR Trans-activation—We have previously shown that the recruitment of p300/ CREBbinding protein (CBP) alone by HTLV-1 Tax is necessary but not sufficient for optimal trans-activation
Summary
Vol 275, No 16, Issue of April 21, pp. 11852–11857, 2000 Printed in U.S.A. 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*. P300/CBP are general integrators of signal-dependent transcription; a diverse array of enhancer-binding factors utilize these co-activators for transcriptional activation in response to extracellular stimuli (49 –53) In addition to their role in facilitating interactions between activators and components of the basal transcription machinery, p300/CBP have been shown to possess intrinsic histone acetyltransferase (HAT) activity [54]. Tax-derived mutants, defective for direct interactions with either of these co-activators, in vitro and in vivo, are defective in their abilities to activate transcription These observations further imply that Tax might influence nuclear P/CAF-containing complexes; thereby potentially contributing to the pleiotropic dysregulated expression of numerous cellular genes during leukemogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
