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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    • "The SIK1-K56M expression vector and the empty vector, pcDNA3, were from Hiroshi Takemori (National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan) [24]. The CRTC1, CRTC2, and CRTC3 vectors as well as the empty vector pcDNA 3.1/V5/HisA were from Dr. Dong-Yan Jin, Department of Biochemistry , The University of Hong Kong [25]. WT CREB (pRc/RSV-Flag- CREB), pRc/RSV-Flag-CREB R314, dominant-negative TORC1 (pcDNA3- TORC1 1-147 -EGFP), and the empty vector pcDNA3-EGFP were from Jean-Rene Cardinaux, University of Lausanne, Lausanne, Switzerland [26]. "
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    ABSTRACT: Sodium reabsorption by the kidney is regulated by locally produced natriuretic and anti-natriuretic factors, including dopamine and norepinephrine, respectively. Previous studies indicated that signaling events initiated by these natriuretic and anti-natriuretic factors achieve their effects by altering the phosphorylation of Na,K-ATPase in the renal proximal tubule, and that Protein Kinase A (PKA) and Calcium mediated signaling pathways are involved. The same signaling pathways also control the transcription of the Na,K-ATPase β subunit gene atp1b1 in renal proximal tubule cells. In this report, evidence is presented that 1) both the recently discovered cAMP-Regulated Transcriptional Coactivators (CRTCs), and Salt Inducible Kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in renal proximal tubule (RPT) cells, and 2) that renal effectors including norepinephrine, dopamine, prostaglandins and sodium play a role. Exogenously expressed CRTCs stimulate atp1b1 transcription. Evidence for a role of endogenous CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant negative CRTC, as well as by a CREB mutant, with an altered CRTC binding site. In a number of experimental systems, SIK phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK in primary RPT cells, atp1b1 transcription increased in the presence of a dominant negative SIK1, and in addition, regulation by dopamine, norepinephrine and monensin was disrupted by a dominant negative SIK1. These latter observations can be explained, if SIK1 is phosphorylated and inactivated in the presence of these renal effectors. Our results support the hypothesis that Na,K-ATPase in the renal proximal tubule is regulated at the transcriptional level via SIK1 and CRTCs by renal effectors, in addition to the previously reported control of the phosphorylation of Na,K-ATPase.
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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.
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