Siu YT, Chin KT, Siu KL, Yee Wai Choy E, Jeang KT, Jin DY.. TORC1 and TORC2 coactivators are required for tax activation of the human T-cell leukemia virus type 1 long terminal repeats. J Virol 80: 7052-7059

Department of Biochemistry, The University of Hong Kong, 3/F Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong.
Journal of Virology (Impact Factor: 4.44). 08/2006; 80(14):7052-9. DOI: 10.1128/JVI.00103-06
Source: PubMed


Human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral transcription from the long terminal repeats (LTR).
Mechanisms through which Tax activates LTR have been established, but coactivators of this process remain to be identified
and characterized. Here we show that all three members of the TORC family of transcriptional regulators are coactivators of
Tax for LTR-driven expression. TORC coactivation requires CREB, but not ATF4 or other bZIP factors. Tax physically interacts
with TORC1, TORC2, and TORC3 (TORC1/2/3), and the depletion of TORC1/2/3 inhibited Tax activity. TORC coactivation can be
further enhanced by transcriptional coactivator p300. In addition, coactivators in the p300 family are required for full activity
of Tax independently of TORC1/2/3. Thus, both TORC and p300 families of coactivators are essential for optimal activation
of HTLV-1 transcription by Tax.

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Available from: Kam-Leung Siu, May 20, 2015
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    • "Additional host factors that directly interact with Tax-1 and act in the Tax-mediated transactivation are the transducer of regulated CREB (TORC) proteins. TORC-1 and TORC-2 are required for Tax activation whereas TORC- 3 enhances Tax-dependent transcription (Koga et al., 2004; Siu et al., 2006). Several cellular factors that interact with Tax and participate to HTLV-1 promoter activation have been identified. "
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    ABSTRACT: Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-κB (nuclear factor kappa-B) pathway, and interactions with host factors.
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    • "Western blotting was carried out as described [13] [28]. Cells were lysed in RIPA buffer (50 mM Tris–HCl, pH 7.4, 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 1% sodium deoxycholate) supplemented with 2 mM PMSF and EDTA-free protease inhibitor cocktail (Roche). "
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    ABSTRACT: Activating transcription factor 4 (ATF4) is a master regulator of genes involved in unfolded protein response (UPR) and its translation is regulated through reinitiation at upstream open reading frames. Here, we demonstrate internal ribosome entry site (IRES)-mediated translation of an alternatively spliced variant of human ATF4. This variant that contains four upstream open reading frames in the 5' leader region was expressed in leukocytes and other tissues. mRNA and protein expression of this variant was activated in the UPR. Its translation was neither inhibited by steric hindrance nor affected by eIF4G1 inactivation, indicating a cap-independent and IRES-dependent mechanism not mediated by ribosome scanning-reinitiation. The IRES activity mapped to a highly structured region that partially overlaps with the third and fourth open reading frames was unlikely attributed to cryptic promoter or splicing, but was activated by PERK-induced eIF2α phosphorylation. Taken together, our findings reveal a new mechanism for translational regulation of ATF4 in mammalian UPR.
    Biochimica et Biophysica Acta 05/2013; 1833(10). DOI:10.1016/j.bbamcr.2013.05.002 · 4.66 Impact Factor
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    • "Dual luciferase assay was carried out as previously described [8,37]. Transfection efficiencies were normalized to pSVRL control plasmid expressing Renilla luciferase (Promega). "
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    ABSTRACT: Background Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized. Results In this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1. Conclusion Group I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.
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