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1
Marti, Francesc, Nicholas H. Post, Elena Chan, and Philip D. King. "A Transcription Function for the T Cell–Specific Adapter (Tsad) Protein in T Cells." Journal of Experimental Medicine 193, no. 12 (June 18, 2001): 1425–30. http://dx.doi.org/10.1084/jem.193.12.1425.
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T cell–specific adapter (TSAd) protein is an Src homology 2 (SH2) domain–containing adapter molecule implicated in T cell receptor for antigen (TCR)-mediated interleukin 2 (IL-2) secretion in T cells. Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus. Nuclear import of TSAd is an active process that depends on TSAd SH2 domain recognition of a phosphotyrosine-containing ligand. Importantly, we show that TSAd can act as a potent transcriptional activator in T cells. Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import. Biochemical analyses suggest that a single TSAd SH2 domain ligand of 95–100 kD may be involved in these processes. Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter–reporter gene construct results in a considerable upregulation of IL-2 promoter activity. Further, we show that this augmentation requires a functional TSAd SH2 domain. However, TSAd does not appear to modulate the activity of the major recognized IL-2 gene transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T cells (NFAT), or activator protein 1 (AP-1). These findings point to the function of TSAd as a novel transcription-regulatory protein in T cells and illustrate the importance of the TSAd SH2 domain in this role.
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Hokello, Joseph, Adhikarimayum Lakhikumar Sharma, and Mudit Tyagi. "Efficient Non-Epigenetic Activation of HIV Latency through the T-Cell Receptor Signalosome." Viruses 12, no. 8 (August 8, 2020): 868. http://dx.doi.org/10.3390/v12080868.
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Human immunodeficiency virus type-1 (HIV-1) can either undergo a lytic pathway to cause productive systemic infections or enter a latent state in which the integrated provirus remains transcriptionally silent for decades. The ability to latently infect T-cells enables HIV-1 to establish persistent infections in resting memory CD4+ T-lymphocytes which become reactivated following the disruption or cessation of intensive drug therapy. The maintenance of viral latency occurs through epigenetic and non-epigenetic mechanisms. Epigenetic mechanisms of HIV latency regulation involve the deacetylation and methylation of histone proteins within nucleosome 1 (nuc-1) at the viral long terminal repeats (LTR) such that the inhibition of histone deacetyltransferase and histone lysine methyltransferase activities, respectively, reactivates HIV from latency. Non-epigenetic mechanisms involve the nuclear restriction of critical cellular transcription factors such as nuclear factor-kappa beta (NF-κB) or nuclear factor of activated T-cells (NFAT) which activate transcription from the viral LTR, limiting the nuclear levels of the viral transcription transactivator protein Tat and its cellular co-factor positive transcription elongation factor b (P-TEFb), which together regulate HIV transcriptional elongation. In this article, we review how T-cell receptor (TCR) activation efficiently induces NF-κB, NFAT, and activator protein 1 (AP-1) transcription factors through multiple signal pathways and how these factors efficiently regulate HIV LTR transcription through the non-epigenetic mechanism. We further discuss how elongation factor P-TEFb, induced through an extracellular signal-regulated kinase (ERK)-dependent mechanism, regulates HIV transcriptional elongation before new Tat is synthesized and the role of AP-1 in the modulation of HIV transcriptional elongation through functional synergy with NF-κB. Furthermore, we discuss how TCR signaling induces critical post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of P-TEFb which enhances interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation.
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Jabeen, Rukhsana, Hua-Chen Chang, Ritobrata Goswami, Stephen L. Nutt, and Mark H. Kaplan. "The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis." PLoS ONE 6, no. 7 (July 14, 2011): e22189. http://dx.doi.org/10.1371/journal.pone.0022189.
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Wang, C. Y., A. G. Bassuk, L. H. Boise, C. B. Thompson, R. Bravo, and J. M. Leiden. "Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors." Molecular and Cellular Biology 14, no. 2 (February 1994): 1153–59. http://dx.doi.org/10.1128/mcb.14.2.1153-1159.1994.
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The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.
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Wang, C. Y., A. G. Bassuk, L. H. Boise, C. B. Thompson, R. Bravo, and J. M. Leiden. "Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors." Molecular and Cellular Biology 14, no. 2 (February 1994): 1153–59. http://dx.doi.org/10.1128/mcb.14.2.1153.
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The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.
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Ai, Di, Jun Wang, Melanie Amen, Mei-Fang Lu, Brad A. Amendt, and James F. Martin. "Nuclear Factor 1 and T-Cell Factor/LEF Recognition Elements Regulate Pitx2 Transcription in Pituitary Development." Molecular and Cellular Biology 27, no. 16 (June 11, 2007): 5765–75. http://dx.doi.org/10.1128/mcb.01848-06.
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ABSTRACT Pitx2, a paired-related homeobox gene that is mutated in Rieger syndrome I, is the earliest known marker of oral ectoderm. Pitx2 was previously shown to be required for tooth, palate, and pituitary development in mice; however, the mechanisms regulating Pitx2 transcription in the oral ectoderm are poorly understood. Here we used an in vivo transgenic approach to investigate the mechanisms regulating Pitx2 transcription. We identified a 7-kb fragment that directs LacZ expression in oral ectoderm and in many of its derivatives. Deletion analysis of transgenic embryos reduced this fragment to a 520-bp region that directed LacZ activity to Rathke's pouch. A comparison of the mouse and human sequences revealed a conserved nuclear factor 1 (NF-1) recognition element near a consensus T-cell factor (TCF)/LEF binding site. The mutation of either site individually abolished LacZ activity in transgenic embryos, identifying Pitx2 as a direct target of Wnt signaling in pituitary development. These findings uncover a requirement for NF-1 and TCF factors in Pitx2 transcriptional regulation in the pituitary and provide insight into the mechanisms controlling region-specific transcription in the oral ectoderm and its derivatives.
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Yang, Zhuoying, and James Douglas Engel. "Human T cell transcription factor GATA-3 stimulates HIV-1 expression." Nucleic Acids Research 21, no. 12 (1993): 2831–36. http://dx.doi.org/10.1093/nar/21.12.2831.
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Wherry, E. John. "Molecular Basis of T-Cell Exhaustion." Blood 122, no. 21 (November 15, 2013): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v122.21.sci-38.sci-38.
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Abstract T-cell exhaustion is common during chronic infections, cancer, exposure to persisting antigens, and can prevent optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T-cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes), in controlling the sustainability and terminal differentiation of exhausted T cell populations. Chronic infections and persisting antigen exposure often strains the sustainability or regenerative capacity of exhausted T cell populations resulting in an eventual collapse in immunity. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. These represent unique functions for T-bet and Eomes since these transcription factors are associated with different roles in functional memory T cells, highlighting the contextual dependence of transcriptional regulation guiding T-cell exhaustion. Additional studies are focusing on the role of other transcription factors such as BATF in T-cell activation and exhaustion, and on the role of inhibitory receptors including PD-1 in shaping the differentiation of exhausted CD8 T-cell subsets. Ultimately, a more precise molecular understanding of T-cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer. Disclosures: Wherry: Genentech: Patents & Royalties.
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Clemens, K. E., G. Piras, M. F. Radonovich, K. S. Choi, J. F. Duvall, J. DeJong, R. Roeder, and J. N. Brady. "Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA." Molecular and Cellular Biology 16, no. 9 (September 1996): 4656–64. http://dx.doi.org/10.1128/mcb.16.9.4656.
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The Tax protein of human T-cell lymphotropic virus type 1 (HTLV-1) is a 40-kDa transcriptional activator which is critical for HTLV-1 gene regulation and virus-induced cellular transformation. Tax is localized to the DNA through its interaction with the site-specific activators cyclic AMP-responsive element-binding protein, NF-kappaB, and serum response factor. It has been suggested that the recruitment of Tax to the DNA positions Tax for interaction with the basal transcriptional machinery. On the basis of several independent assays, we now report a physical and functional interaction between Tax and the transcription factor, TFIIA. First, Tax was found to interact with the 35-kDa (alpha) subunit of TFIIA in the yeast two-hybrid interaction system. Importantly, two previously characterized mutants with point mutations in Tax, M32 (Y196A, K197S) and M41 (H287A, P288S), which were shown to be defective in Tax-activated transcription were unable to interact with TFIIA in this assay. Second, a glutathione-S-transferase (GST) affinity-binding assay showed that the interaction of holo-TFIIA with GST-Tax was 20-fold higher than that observed with either the GST-Tax M32 activation mutant or the GST control. Third, a coimmunoprecipitation assay showed that in HTLV-1-infected human T lymphocytes, Tax and TFIIA were associated. Finally, TFIIA facilitates Tax transactivation in vitro and in vivo. In vitro transcription studies showed reduced levels of Tax-activated transcription in cell extracts depleted of TFIIA. In addition, transfection of human T lymphocytes with TFIIA expression vectors enhanced Tax-activated transcription of an HTLV-1 long terminal repeat-chloramphenicol acetyltransferase reporter construct. Our study suggests that the interaction of Tax with the transcription factor TFIIA may play a role in Tax-mediated transcriptional activation.
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Gounari, Fotini, and Marei Dose. "Lef-1: NOTCHed up in T-cell lymphomas." Blood 110, no. 7 (October 1, 2007): 2227. http://dx.doi.org/10.1182/blood-2007-07-100156.
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In this issue of Blood, Spaulding and colleagues show that Lef-1, one of the transcription factors mediating Wnt signaling, is a transcriptional target of Notch in T-cell lymphomas. Notch-activating mutations are commonly found in human T-lineage acute lymphoblastic leukemia (T-ALL) cases, while activation of Wnt/β-catenin signaling has recently been shown to induce T-cell leukemia in mice. The proposed regulation of Lef-1 transcription by Notch suggests the intriguing possibility that the Notch and Wnt pathways are closely intertwined in the etiology of T-cell leukemia.
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Fortin, Jean-François, Benoit Barbeau, Gilles A. Robichaud, and Michel J. Tremblay. "T Cell Activation and Regulation of HIV-1: Same Effectors with Distinct Outcomes." Canadian Journal of Infectious Diseases 10, suppl c (1999): 25C—32C. http://dx.doi.org/10.1155/1999/717641.
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The molecular mechanisms that regulate the function of the immune system and human immunodeficiency virus type-1 (HIV-1) gene expression are diverse and complicated. However, replication of HIV-1 is controlled by many of the same regulatory signals that play a crucial role in the transcriptional regulation of the immune system. For example, the viral promoter, as is the case for the immune system, is subject to complex regulation by combinations of cellular transcription factors that may quantitatively and/or qualitatively differ depending on cell types (eg, macrophages versus T lymphocytes) and cell states (eg, undifferentiated versus differentiated or quiescent versus activated). The present review discusses the regulation of HIV-1 gene expression by nuclear factor-kappa Band nuclear factor of activated T cells, and proposes that selective interference of these two cellular transcription factors may be a route to abrogate virus replication without disrupting normal cellular functions. A better understanding of the regulation of HIV-1 gene expression is of utmost importance for the design of molecular approaches that will effectively abrogate virus replication and, ultimately, disease progression.
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Ho, N., M. Gullberg, and T. Chatila. "Activation protein 1-dependent transcriptional activation of interleukin 2 gene by Ca2+/calmodulin kinase type IV/Gr." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 101–12. http://dx.doi.org/10.1084/jem.184.1.101.
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The Ca2+/calmodulin-dependent protein kinase (CaMK) type IV/Gr is selectively expressed in T lymphocytes and is activated after signaling via the T cell antigen receptor (TCR), indicating that it mediates some of the Ca(2+)-dependent transcriptional events that follow TCR engagement. Here we show that CaMKIV/Gr induces the transcription factor activation protein 1 (AP-1) alone or in synergy with T cell mitogens and with the p21ras oncoprotein. CaMKIV/ Gr signaling is associated with transcriptional activation of c-fos but is independent of p21ras or calcineurin. AP-1 is an integral component of the nuclear factor of activated T cells (NFAT) transcriptional complex, which is required for interleukin 2 gene expression in T cells. We demonstrate that CaMKIV/Gr reconstitutes the capacity of the cytosolic component of NFAT to direct transcription from NFAT sites in non-T cells. These results reveal a central role for CaMKIV/Gr as a Ca(2+)-regulated activator of gene transcription in T lymphocytes.
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Kriegova, E., R. Fillerova, T. Tomankova, B. Hutyrova, F. Mrazek, T. Tichy, V. Kolek, R. M. du Bois, and M. Petrek. "T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis." European Respiratory Journal 38, no. 5 (May 3, 2011): 1136–44. http://dx.doi.org/10.1183/09031936.00089910.
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Tang, Hei-Man Vincent, Wei-Wei Gao, Chi-Ping Chan, Yun Cheng, Jian-Jun Deng, Kit-San Yuen, Hidekatsu Iha, and Dong-Yan Jin. "SIRT1 Suppresses Human T-Cell Leukemia Virus Type 1 Transcription." Journal of Virology 89, no. 16 (June 10, 2015): 8623–31. http://dx.doi.org/10.1128/jvi.01229-15.
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ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-κB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV-1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes. Suppressing HTLV-1 gene expression might have preventive and therapeutic benefits. It is therefore critical that host factors controlling HTLV-1 gene expression be identified and characterized. This work reveals a new host factor that suppresses HTLV-1 gene expression and a natural compound that activates this suppression. Our findings not only provide new knowledge of the host control of HTLV-1 gene expression but also suggest a new strategy of using natural compounds for prevention and treatment of HTLV-1-associated diseases.
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Zhao, Tiejun, Yorifumi Satou, Kenji Sugata, Paola Miyazato, Patrick L. Green, Takeshi Imamura, and Masao Matsuoka. "HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator." Blood 118, no. 7 (August 18, 2011): 1865–76. http://dx.doi.org/10.1182/blood-2010-12-326199.
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Abstract Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.
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Lemasson, Isabelle, Nicholas J. Polakowski, Paul J. Laybourn, and Jennifer K. Nyborg. "Transcription Factor Binding and Histone Modifications on the Integrated Proviral Promoter in Human T-cell Leukemia Virus-I-infected T-cells." Journal of Biological Chemistry 277, no. 51 (October 16, 2002): 49459–65. http://dx.doi.org/10.1074/jbc.m209566200.
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The human T-cell leukemia virus (HTLV-I)-encoded Tax protein is a potent transcriptional activator that stimulates expression of the integrated provirus. Biochemical studies indicate that Tax, together with cellular transcription factors, interacts with viral cAMP-response element enhancer elements to recruit the pleiotropic coactivators CREB-binding protein and p300. Histone acetylation by these coactivators has been shown to play a major role in activating HTLV-I transcription from chromatin templatesin vitro. However, the extent of histone modification and the precise identity of the cellular regulatory proteins bound at the HTLV-I promoterin vivois not known. Chromatin immunoprecipitation analysis was used to investigate factor binding and histone modification at the integrated HTLV-I provirus in infected T-cells (SLB-1). These studies reveal the presence of Tax, a variety of ATF/CREB and AP-1 family members (CREB, CREB-2, ATF-1, ATF-2, c-Fos, and c-Jun), and both p300 and CREB-binding protein at the HTLV-I promoter. Consistent with the binding of these coactivators, we observed histone H3 and H4 acetylation at three regions within the proviral genome. Histone deacetylases were also present at the viral promoter and, following their inhibition, we observe an increase in histone H4 acetylation on the HTLV-I promoter and a concomitant increase in viral RNA. Together, these results suggest that a variety of transcriptional activators, coactivators, and histone deacetylases participate in the regulation of HTLV-I transcription in infected T-cells.
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Zúñiga-Pflücker, J. C., H. L. Schwartz, and M. J. Lenardo. "Gene transcription in differentiating immature T cell receptor(neg) thymocytes resembles antigen-activated mature T cells." Journal of Experimental Medicine 178, no. 4 (October 1, 1993): 1139–49. http://dx.doi.org/10.1084/jem.178.4.1139.
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Early in ontogeny thymocytes have a surface marker phenotype that resembles activated mature T cells but they lack expression of the T cell receptor (TCR) complex. We have made preparations of day 14/15 triple negative fetal thymocytes that exhibit the activated T lymphocyte markers CD25, intercellular adhesion molecule 1, Ly-6A/E, CD44, and heat stable antigen and are rapidly proliferating as evidenced by flow cytometric examination of BrdU incorporation. We found that binding activities of the gene regulators nuclear factor (NF)-kappa B, the NF-kappa B p50 homodimer complex, nuclear factor of activated T cells (NF-AT), oct-1, oct-2, activator protein 1 (AP-1), and serum response factor (SRF), are all present in these early thymocytes. Whereas the octamer factors and SRF persist during ontogeny, NF-kappa B, NF-AT, and AP-1 decrease and are undetectable in the adult thymus. Transfection of disaggregated thymocytes by electroporation or intact thymic lobes by gold-particle bombardment revealed that reporter constructs for NF-kappa B, NF-AT, AP-1, octamer factors and, to a small extent, the TCR-alpha enhancer were active in early thymocyte development. We rigorously eliminated the possibility that these transcriptional events were due to minor populations of TCR+ cells by showing that these reporter constructs were also active in recombinase activating gene (RAG)-/- thymocytes that are incapable of completing TCR gene rearrangement, and predominantly contain cells that have an activated phenotype. Thus, transcriptional events that are usually triggered by antigen stimulation in mature T cells take place early in thymic ontogeny in the absence of the TCR. Our analysis suggests that there are striking regulatory similarities but also important differences between the activation processes that take place in antigen-stimulated mature T cells and thymic progenitor cells.
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Fujii, Masahiro, Kousuke Iwai, Masayasu Oie, Masaya Fukushi, Naoki Yamamoto, Mari Kannagi, and Naoki Mori. "Activation of Oncogenic Transcription Factor AP-1 in T Cells Infected with Human T Cell Leukemia Virus Type 1." AIDS Research and Human Retroviruses 16, no. 16 (November 2000): 1603–6. http://dx.doi.org/10.1089/08892220050193029.
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Gruda, M. C., J. M. Zabolotny, J. H. Xiao, I. Davidson, and J. C. Alwine. "Transcriptional activation by simian virus 40 large T antigen: interactions with multiple components of the transcription complex." Molecular and Cellular Biology 13, no. 2 (February 1993): 961–69. http://dx.doi.org/10.1128/mcb.13.2.961-969.1993.
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Simian virus 40 (SV40) large T antigen is a potent transcriptional activator of both viral and cellular promoters. Within the SV40 late promoter, a specific upstream element necessary for T-antigen transcriptional activation is the binding site for transcription-enhancing factor 1 (TEF-1). The promoter structure necessary for T-antigen-mediated transcriptional activation appears to be simple. For example, a promoter consisting of upstream TEF-1 binding sites (or other factor-binding sites) and a downstream TATA or initiator element is efficiently activated. It has been demonstrated that transcriptional activation by T antigen does not require direct binding to the DNA; thus, the most direct effect that T antigen could have on these simple promoters would be through protein-protein interactions with either upstream-bound transcription factors, the basal transcription complex, or both. To determine whether such interactions occur, full-length T antigen or segments of it was fused to the glutathione-binding site (GST fusions) or to the Gal4 DNA-binding domain (amino acids 1 to 147) (Gal4 fusions). With the GST fusions, it was found that TEF-1 and the TATA-binding protein (TBP) bound different regions of T antigen. A GST fusion containing amino acids 5 to 172 (region T1) efficiently bound TBP. TEF-1 bound neither region T1 nor a region between amino acids 168 and 373 (region T2); however, it bound efficiently to the combined region (T5) containing amino acids 5 to 383.(ABSTRACT TRUNCATED AT 250 WORDS)
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Watters, Karen M., Jonathan Dean, Virginie Gautier, William W. Hall, and Noreen Sheehy. "Tax 1-Independent Induction of Vascular Endothelial Growth Factor in Adult T-Cell Leukemia Caused by Human T-Cell Leukemia Virus Type 1." Journal of Virology 84, no. 10 (March 17, 2010): 5222–28. http://dx.doi.org/10.1128/jvi.02166-09.
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ABSTRACT Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). Elevated expression of vascular endothelial growth factor (VEGF) in ATL patients is associated with leukemic cell invasion and infiltration in different organs. The regulatory protein Tax 1 encoded by HTLV-1 plays a pivotal role in T-cell transformation by deregulating the function and expression of several cellular factors. In the present study, we examined the effect of Tax 1 on VEGF expression at transcriptional and posttranscriptional levels in order to elucidate the regulatory mechanisms involved. Using functional assays, we demonstrate that Tax 1 downregulates the VEGF promoter through a cluster of Sp1 sites located close to the transcriptional start site. Using gel mobility shift assays, we show that Tax 1 reduced Sp1:DNA complex formation. We demonstrate that the level of secreted VEGF was significantly lower in Tax 1-transfected 293T cells compared to nontransfected cells, which is consistent with the observed downregulatory effect of Tax 1 at the transcription level. We showed that VEGF was secreted by HTLV-1-transformed and nontransformed cells, irrespective of Tax 1 expression. Overall our data indicate that, contrary to a previous report, Tax 1 downregulates VEGF expression and suggest there are Tax 1-independent mechanisms of VEGF activation in ATL.
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Kim, Chulwoo, Jun Jin, Cornelia M. Weyand, and Jörg J. Goronzy. "The Transcription Factor TCF1 in T Cell Differentiation and Aging." International Journal of Molecular Sciences 21, no. 18 (September 5, 2020): 6497. http://dx.doi.org/10.3390/ijms21186497.
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The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.
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Wurster, A. L., G. Siu, J. M. Leiden, and S. M. Hedrick. "Elf-1 binds to a critical element in a second CD4 enhancer." Molecular and Cellular Biology 14, no. 10 (October 1994): 6452–63. http://dx.doi.org/10.1128/mcb.14.10.6452.
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The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Sp1, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-1, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.
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Wurster, A. L., G. Siu, J. M. Leiden, and S. M. Hedrick. "Elf-1 binds to a critical element in a second CD4 enhancer." Molecular and Cellular Biology 14, no. 10 (October 1994): 6452–63. http://dx.doi.org/10.1128/mcb.14.10.6452-6463.1994.
Full textAbstract:
The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Sp1, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-1, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.
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Zheng, Wenting, Jun Wei, Caitlin C. Zebley, Lindsay L. Jones, Yogesh Dhungana, Yong-Dong Wang, Jayadev Mavuluri, et al. "Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR–T-cell responses against ALL." Blood 138, no. 2 (March 10, 2021): 122–35. http://dx.doi.org/10.1182/blood.2020009309.
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Abstract Chimeric antigen receptor (CAR)–T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR–T-cell expansion and memory-like cell formation. This leads to improved CAR-T–mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1–deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR–T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1− CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR–T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR–T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR–T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.
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Carr, Tiffany, Veena Krishnamoorthy, Shuyang Yu, Hai-Hui Xue, Barbara L. Kee, and Mihalis Verykokakis. "The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation." Journal of Experimental Medicine 212, no. 5 (April 20, 2015): 793–807. http://dx.doi.org/10.1084/jem.20141849.
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Invariant natural killer T cells (iNKT cells) are innate-like T cells that rapidly produce cytokines that impact antimicrobial immune responses, asthma, and autoimmunity. These cells acquire multiple effector fates during their thymic development that parallel those of CD4+ T helper cells. The number of Th2-type effector iNKT cells is variable in different strains of mice, and their number impacts CD8 T, dendritic, and B cell function. Here we demonstrate a unique function for the transcription factor lymphoid enhancer factor 1 (LEF1) in the postselection expansion of iNKT cells through a direct induction of the CD127 component of the receptor for interleukin-7 (IL-7) and the transcription factor c-myc. LEF1 also directly augments expression of the effector fate–specifying transcription factor GATA3, thus promoting the development of Th2-like effector iNKT cells that produce IL-4, including those that also produce interferon-γ. Our data reveal LEF1 as a central regulator of iNKT cell number and Th2-type effector differentiation.
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Anose, Bynthia M., and Michel M. Sanders. "Androgen Receptor Regulates Transcription of the ZEB1 Transcription Factor." International Journal of Endocrinology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/903918.
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The zinc finger E-box binding protein 1 (ZEB1) transcription factor belongs to a two-member family of zinc-finger homeodomain proteins involved in physiological and pathological events mostly relating to cell migration and epithelial to mesenchymal transitions (EMTs). ZEB1 (also known as δEF1, zfhx1a, TCF8, and Zfhep) plays a key role in regulating such diverse processes as T-cell development, skeletal patterning, reproduction, and cancer cell metastasis. However, the factors that regulate its expression and consequently the signaling pathways in which ZEB1 participates are poorly defined. Because it is induced by estrogen and progesterone and is high in prostate cancer, we investigated whethertcf8, which encodes ZEB1, is regulated by androgen. Data herein demonstrate thattcf8is induced by dihydrotestosterone (DHT) in the human PC-3/AR prostate cancer cell line and that this induction is mediated by two androgen response elements (AREs). These results demonstrate that ZEB1 is an intermediary in androgen signaling pathways.
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Olabisi, Opeyemi A., Noemi Soto-Nieves, Edward Nieves, Teddy T. C. Yang, XiaoYong Yang, Raymond Y. L. Yu, Hee Yun Suk, Fernando Macian, and Chi-Wing Chow. "Regulation of Transcription Factor NFAT by ADP-Ribosylation." Molecular and Cellular Biology 28, no. 9 (February 25, 2008): 2860–71. http://dx.doi.org/10.1128/mcb.01746-07.
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ABSTRACT ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1 −/− T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.
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van de Wetering, M., M. Oosterwegel, F. Holstege, D. Dooyes, R. Suijkerbuijk, A. Geurts van Kessel, and H. Clevers. "The human T cell transcription factor-1 gene. Structure, localization, and promoter characterization." Journal of Biological Chemistry 267, no. 12 (April 1992): 8530–36. http://dx.doi.org/10.1016/s0021-9258(18)42476-3.
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Roux, Arthur, Héloise Leroy, Bénédicte De Muylder, Lucie Bracq, Samia Oussous, Isabelle Dusanter-Fourt, Ghina Chougui, et al. "FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction." PLOS Pathogens 15, no. 5 (May 1, 2019): e1007669. http://dx.doi.org/10.1371/journal.ppat.1007669.
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Seo, Hyungseok, Joyce Chen, Edahí González-Avalos, Daniela Samaniego-Castruita, Arundhoti Das, Yueqiang H. Wang, Isaac F. López-Moyado, et al. "TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion." Proceedings of the National Academy of Sciences 116, no. 25 (May 31, 2019): 12410–15. http://dx.doi.org/10.1073/pnas.1905675116.
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T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive (“exhausted” or “dysfunctional”) within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8+ T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8+ CAR+ PD-1high TIM3high (“exhausted”) tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation-associated nuclear factor κB (NFκB) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8+ T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.
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Colgin, Mark A., and Jennifer K. Nyborg. "The Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax Inhibits the Transcriptional Activity of c-Myb through Competition for the CREB Binding Protein." Journal of Virology 72, no. 11 (November 1, 1998): 9396–99. http://dx.doi.org/10.1128/jvi.72.11.9396-9399.1998.
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ABSTRACT Tax, the transforming protein of human T-cell leukemia virus type 1 (HTLV-1), is required for strong activation of HTLV-1 transcription. This activation is mediated through interaction with the KIX domain of the cellular coactivator CREB binding protein (CBP). In this study we examined the possibility that the Tax-KIX interaction may mediate effects on cellular gene transcription in vivo, as a growing number of cellular transcription factors have been shown to utilize CBP as a coactivator. We tested the ability of Tax to deregulate the activity of the cellular transcription factor, c-Myb, since both Tax and c-Myb interact with the KIX domain of CBP. Our results show that in vivo, Tax antagonizes the transcriptional activity of c-Myb and, reciprocally, c-Myb antagonizes the transcriptional activity of Tax. Furthermore, c-Myb competes for KIX binding to Tax in vitro, indicating that these two transcription factors bind CBP in a mutually exclusive manner. This novel mechanism of transcriptional interference by Tax may promote globally deregulated cellular gene expression in the HTLV-1-infected cell, possibly leading to leukemogenesis.
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Niu, Huifeng, Giorgio Cattoretti, and Riccardo Dalla-Favera. "BCL6 Controls the Expression of the B7-1/CD80 Costimulatory Receptor in Germinal Center B Cells." Journal of Experimental Medicine 198, no. 2 (July 14, 2003): 211–21. http://dx.doi.org/10.1084/jem.20021395.
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The BCL6 proto-oncogene encodes a transcriptional repressor required for the development of germinal centers (GCs) and implicated in the pathogenesis of GC-derived B cell lymphoma. Understanding the precise role of BCL6 in normal GC formation and in lymphomagenesis depends on the identification of genes that are direct targets of its transcriptional repression. Here we report that BCL6 directly controls the expression of B7–1/CD80, a costimulatory receptor involved in B–T cell interactions critical for the development of T cell–mediated antibody responses. Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-κB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-κB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development. In addition, these findings imply that T–B cell interactions may be disrupted in B cell lymphoma expressing deregulated BCL6 genes.
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Papavassiliou, Athanasios G., and Anna Maria Musti. "The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion." Cells 9, no. 11 (November 13, 2020): 2470. http://dx.doi.org/10.3390/cells9112470.
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c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.
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Monteleone, I. "Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa." Gut 53, no. 8 (August 1, 2004): 1090–95. http://dx.doi.org/10.1136/gut.2003.030551.
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Koch, Meghan A., Glady's Tucker-Heard, Nikole R. Perdue, Justin R. Killebrew, Kevin B. Urdahl, and Daniel J. Campbell. "The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation." Nature Immunology 10, no. 6 (May 3, 2009): 595–602. http://dx.doi.org/10.1038/ni.1731.
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Willinger, Tim, Tom Freeman, Mark Herbert, Hitoshi Hasegawa, Andrew J. McMichael, and Margaret F. C. Callan. "Human Naive CD8 T Cells Down-Regulate Expression of the WNT Pathway Transcription Factors Lymphoid Enhancer Binding Factor 1 and Transcription Factor 7 (T Cell Factor-1) following Antigen Encounter In Vitro and In Vivo." Journal of Immunology 176, no. 3 (January 19, 2006): 1439–46. http://dx.doi.org/10.4049/jimmunol.176.3.1439.
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Postigo, Antonio A., and Douglas C. Dean. "Independent Repressor Domains in ZEB Regulate Muscle and T-Cell Differentiation." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 7961–71. http://dx.doi.org/10.1128/mcb.19.12.7961.
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ABSTRACT ZEB is a zinc finger-homeodomain protein that represses transcription by binding to a subset of E-box sequences. ZEB inhibits muscle differentiation in mammalian systems, and itsDrosophila orthologue, zfh-1, inhibits somatic and cardiac muscle differentiation during Drosophilaembryogenesis. ZEB also binds to the promoter of pivotal hematopoietic genes (including those encoding interleukin-2, CD4, GATA-3, and α4-integrin), and mice in which ZEB has been genetically targeted show thymic atrophy, severe defects in lymphocyte differentiation, and increased expression of the α4-integrin and CD4. Here, we demonstrate that ZEB contains separate repressor domains which function in T lymphocytes and muscle, respectively. The most C-terminal domain inhibits muscle differentiation in mammalian cells by specifically blocking the transcriptional activity of the myogenic factor MEF2C. The more N-terminal domain blocks activity of hematopoietic transcription factors such as c-myb, members of the etsfamily, and TFE-III. Our results demonstrate that ZEB has evolved with two independent repressor domains which target distinct sets of transcription factors and function in different tissues.
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Tüfekçi, Özlem, Melis Kartal Yandım, Hale Ören, Gülersu Irken, and Yusuf Baran. "Targeting FOXM1 Transcription Factor In T-Cell Acute Lymphoblastic Leukemia." Blood 122, no. 21 (November 15, 2013): 4974. http://dx.doi.org/10.1182/blood.v122.21.4974.4974.
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Abstract The Forkhead box protein M1(FoxM1) is an important transcriptional factor that takes play in regulation of cell cyle, proliferation, DNA repair, apoptosis, and angiogenesis. FoxM1 overexpression has been reported to be related with many types of cancer. Since many studies have reported that FOXM1 is an important target for cancer therapy, many researchers are studying on the identification of FOXM1 inhibitors. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. Dexamethasone is a glucocorticoid that is very important in treatment of acute lymphoblastic leukemia (ALL) and is known to be more potent compared to other steroids in the treatment of T-cell ALL. In this study, our aims were to determine the gene expression levels of FoxM1 in Jurkat cells (T-ALL cell line), to find out the possible synergistic and apoptotic effects of siomycin A and dexamethasone on this cell line and to investigate the changes in expression profiles of some important genes that have vital roles in cellular processes by targeting FoxM1 with siomycin A and dexamethasone on Jurkat cells. The gene expression levels of FoxM1 were studied with reverse transcriptase polymerase chain reaction (RT-PCR). The cytotoxic effects of siomycin A and dexamethasone on Jurkat cells were assesed by MTT cell proliferation test. The possible synergistic, additive, neutral, and antagonistic effect of combination of dexamethasone and siomycin A was determined with isobologram analysis. The apoptotic effects of these two agents were evaluated by Caspase-3 activity, loss of mitochondrial membrane potential and localisation of phosphatidilserine on plasma membrane. For this purpose, Caspase-3 calorimetric assay kit, JC-1 mitochondrial membrane potential assay kit, and Annexin V-FITC apoptosis detection kit were used, respectively. For cell cycle analysis, Jurkat cells treated with siomycin A alone or in combination with dexamethasone were stained by propidium iodide and then analyzed by flow cytometry. Expression profiles of Jurkat cells treated with siomycin A alone or in combination with dexamethasone were determined by Cancer Pathway Finder PCR Array. We found that FoxM1 gene is overexpressed in T-ALL cell line and dexamethasone and siomycin A caused a reduction in gene expression levels of FoxM1 in Jurkat cells. 8% to 13% decrease in proliferation of Jurkat cells were observed when these cells were treated with 1 and 10 µM doses of dexamethasone for 72 hours, respectively. The same doses of dexamethasone combined with siomycin A caused 74% and 75% decrease in proliferation of Jurkat cells. Isobologram analysis revealed very strong synergy between dexamethasone and siomycin A. Apoptotic tests showed no apoptotic activity of dexamethasone and siomycin A on Jurkat cells. Cell cycle analysis demonstrated that, reduction of FOXM1 expression by combination of dexamethasone and siomycin A in Jurkat cells inhibited cell proliferation through induction of G1 phase arrest. PCR Array results showed that apoptotic CASPASE-2, CASPASE-7, and CASPASE-9 genes and XIAP and CYCLIN D3 genes were upregulated in response to the treatment. ETS2 gene, which is known as a protooncogene and shown to be involved in regulation of telomerase, was downregulated in response to siomycin A and dexamethosone alone and in combined treatment. TERF1 gene, which inhibits telomerase activity, was upregulated by the treatment. Combination of Siomycin A and dexamethasone downregulated the MCM-2 gene, which is a key component of the pre-replication complex and involved in the formation of DNA replication fork. Moreover, combined treatment resulted in the downregulation of MKI67 gene encoding a nuclear protein associated with cellular proliferation. WEE1 gene, which inhibits G2/M phase transition in cell cycle, was also upregulated. These data indicate that FoxM1 gene is strongly overexpressed in T-ALL cell line and targeting FoxM1 by siomycin A and dexamethasone causes a significant decrease in T-ALL cell proliferation through induction of G1 cell cycle arrest. Importantly, PCR array analyses also showed that siomycin A and dexamethasone treatment affects Jurkat cells via upregulating or downregulating the key genes of cell cycle, apoptosis, cell proliferation, telomere, and telomerase function. All these findings suggest a possible role for FoxM1 in T-ALL pathogenesis and represent FoxM1 as an attractive target for T-ALL therapy. Disclosures: No relevant conflicts of interest to declare.
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Kennell, Jennifer A., Erin E. O'Leary, Brian M. Gummow, Gary D. Hammer, and Ormond A. MacDougald. "T-Cell Factor 4N (TCF-4N), a Novel Isoform of Mouse TCF-4, Synergizes with β-Catenin To Coactivate C/EBPα and Steroidogenic Factor 1 Transcription Factors." Molecular and Cellular Biology 23, no. 15 (August 1, 2003): 5366–75. http://dx.doi.org/10.1128/mcb.23.15.5366-5375.2003.
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ABSTRACT We have cloned T-cell factor 4N (TCF-4N), an alternative isoform of TCF-4, from developing pituitary and 3T3-L1 preadipocytes. This protein contains the N-terminal interaction domain for β-catenin but lacks the DNA binding domain. While TCF-4N inhibited coactivation by β-catenin of a TCF/lymphoid-enhancing factor (LEF)-dependent promoter, TCF-4N potentiated coactivation by β-catenin of several non-TCF/LEF-dependent promoters. For example, TCF-4N synergized with β-catenin to activate the α-inhibin promoter through functional and physical interactions with the orphan nuclear receptor steroidogenic factor 1 (SF-1). In addition, TCF-4N and β-catenin synergized with the adipogenic transcription factor CCAAT/enhancer binding protein α (C/EBPα) to induce leptin promoter activity. The mechanism by which β-catenin and TCF-4N coactivated C/EBPα appeared to involve p300, based upon synergy between these important transcriptional regulators. Consistent with TCF-4N′s redirecting the actions of β-catenin in cells, ectopic expression of TCF-4N in 3T3-L1 preadipocytes partially relieved the block of adipogenesis caused by β-catenin. Thus, we propose that TCF-4N inhibits coactivation by β-catenin of TCF/LEF transcription factors and potentiates the coactivation by β-catenin of other transcription factors, such as SF-1 and C/EBPα.
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Robek, Michael D., and Lee Ratner. "Immortalization of CD4+ and CD8+ T Lymphocytes by Human T-Cell Leukemia Virus Type 1 Tax Mutants Expressed in a Functional Molecular Clone." Journal of Virology 73, no. 6 (June 1, 1999): 4856–65. http://dx.doi.org/10.1128/jvi.73.6.4856-4865.1999.
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ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) transcriptionaltrans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models. In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-κB pathway of transcriptional activation. The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-κB or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-κB pathway may be critical.
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Alcaide, Pilar, Tatiana G. Jones, Graham M. Lord, Laurie H. Glimcher, Jenny Hallgren, Yojiro Arinobu, Koichi Akashi, Alison M. Paterson, Michael A. Gurish, and Francis W. Luscinskas. "Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue." Journal of Experimental Medicine 204, no. 2 (February 12, 2007): 431–39. http://dx.doi.org/10.1084/jem.20060626.
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The transcription factor T-bet was identified in CD4+ T cells, and it controls interferon γ production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432–3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet−/− mice is reduced. This is reproduced in adhesion studies using bone marrow–derived MCs (BMMCs) from T-bet−/− mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule–1 (MAdCAM-1) and vascular cell adhesion molecule–1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet−/− mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet−/− mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues.
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Fang, Fang, Mangju Wang, Quan Qiu, Dingfang Bu, Wei Liu, Ying Zhang, Yongjin Shi, Xuzhen Lv, and Ping Zhu. "Human Transcription Factor KLF3 Maintains T Lymphocyte Quiescent Phenotype Via Inhibiting SHP-1 Expression." Blood 126, no. 23 (December 3, 2015): 3426. http://dx.doi.org/10.1182/blood.v126.23.3426.3426.
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Abstract Quiescent state of lymphocyte is a critical mechanism for immunity homeostasis. Until recently it has been recognized that quiescent state is not a passive default mode which also needs many signal molecular and transcriptional factors involvement. However, the mechanism of T cell quiescence remains incompletely understood. In quiescent cell, KLF3 is a highly expressed transcriptional factor, but once T lymphocyte is activated, KLF3 expression is reduced to an undetectable level. The Src homology 2 domain tyrosine phosphatase (SHP-1) is mainly expressed in hematopoietic cells and has been known to plays a negative effect on T cell activation. SHP-1 mutant mice (SHP-1me/me) exhibits multiple hematopoietic cells proliferation disorder and systemic inflammation. Compare to SHP-1me/me mice, KLF3 knock-out mice shows a myeloproliferative disorder and systematic inflammatory responses likewise. Accumulating evidence indicates KLF3 is a crucial transcription factor in T cell quiescent. Based on similarity between SHP-1me/me mice and KLF3 knock-out mice, we explore whether KLF3 cooperate with SHP-1 to maintain cell quiescence. SHP-1 consists two promoter regions that one locates upstream of exon1, mainly expressed in epithelial cell and the other one locates in intron 1 which mainly serves for hematopoietic cell. According to literature, the core promoter element which plays a critical role in SHP-1 gene regulation locates upstream 120bp of transcriptional site. Two cacc boxes (5'---caccc----3') were found among the core promoter elements. We constructed a reporter gene vector named pGL3-SHP1-luci1 which consist two cacc boxes. We also constructed another three vectors based on pGL3-SHP1-luci1. (figure1 left). We process dual-luciferase assay at 72h post transfection (figure1 right). when the proximal cacc box is mutated, the promoter activity is 1.7 times as high as the promoter activity of normal promoter sequence (luci1 vector) (p<0.05). The transcription factor KLF3 functions as a repressor to interact with SHP-1 P2 promoter. We prepare two dioxin-labelled probes based on cacc box motif to verify the binding activities between KLF3 and SHP-1. The probe I is consist of the distal cacc box and the probe II possesses the proximal cacc box. Two specific bands (A,B)were observed when probe target I or target II was adding into DNA-protein mixture (Figure2, lane2, 5). This band specifically disappeared by the addition of excess unlabeled target as a competitor (Figure2, lane 3, 6) which indicates probe can be a target of nuclear proteins from Jurkat cell. To verify KLF3 is the transcription factor involving in the interaction with labelled-probe, we added anti-KLF3 antibody to the EMSA binding reaction. The results show band A disappeared in the presence of target I and it became weaker in the presence of target II, but band B were still present after addition of anti-KLF3 antibody to the mixture (Figure2, lane4, 8). The band A, but not band B, disappeared or become weaken in the presence of anti-KLF3 antibody, indicates KLF3 interacts with SHP-1 P2 promoter. To test the ability of KLF3 binding to SHP-1 promoter 2 (P2) in vivo, we performed chromatin immunoprecipitation (ChIP) analysis using antibodies for KLF3 and compared it with the IgG-negative control. We design one promoter primer targeting a region from -135bp to 53bp which contains a potential KLF3 binding site and one SHP-1 exon15 promoter as a control for antibody enriched DNA analysis. By promoter primer or exon15 primer, specific DNA bands were observed in input. However, only anti-KLF3 enriched DNA can amplify a specific band with promoter primer. By contrast, the IgG negative control enriched DNA fail to amplify positive bands with promoter primer. And for the exon15 primer, it hardly amplified positive bands neither from anti-KLF3-enriched DNA nor from IgG negative control-enriched DNA (figure3). These data demonstrates that KLF3 proteins directly regulate SHP-1 expression. Our study suggests KLF3, as the candidate of programing T cell quiescence, can regulate SHP-1 to maintain quiescent phenotype. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.
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Chen, Shaoqiong, Denis C. Guttridge, Zongbing You, Zhaochen Zhang, Andrew Fribley, Marty W. Mayo, Jan Kitajewski, and Cun-Yu Wang. "WNT-1 Signaling Inhibits Apoptosis by Activating β-Catenin/T Cell Factor–Mediated Transcription." Journal of Cell Biology 152, no. 1 (January 8, 2001): 87–96. http://dx.doi.org/10.1083/jcb.152.1.87.
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Wnt signaling plays a critical role in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of Wnt signaling, little is known regarding Wnt signaling modification of the cell death machinery. Given that numerous oncogenes transform cells by providing cell survival function, we hypothesized that Wnt signaling may inhibit apoptosis. Here, we report that cells expressing Wnt-1 were resistant to cancer therapy–mediated apoptosis. Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that Wnt-1–mediated cell survival was dependent on the activation of β-catenin/T cell factor (Tcf) transcription. Inhibition of β-catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1–mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results provide the first demonstration that Wnt-1 inhibits cancer therapy–mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mechanism of anti-apoptosis.
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Garcia-Perez, Laura, Farbod Famili, Martijn Cordes, Martijn Brugman, Marja van Eggermond, Haoyu Wu, Jihed Chouaref, et al. "Functional definition of a transcription factor hierarchy regulating T cell lineage commitment." Science Advances 6, no. 31 (July 2020): eaaw7313. http://dx.doi.org/10.1126/sciadv.aaw7313.
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T cell factor 1 (Tcf1) is the first T cell–specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell–committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.
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Murata, Takayuki, Chieko Noda, Yohei Narita, Takahiro Watanabe, Masahiro Yoshida, Keiji Ashio, Yoshitaka Sato, et al. "Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor." Journal of Virology 90, no. 8 (January 27, 2016): 3873–89. http://dx.doi.org/10.1128/jvi.03227-15.
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ABSTRACTLatent membrane protein 1 (LMP1) is a major oncogene essential for primary B cell transformation by Epstein-Barr virus (EBV). Previous studies suggested that some transcription factors, such as PU.1, RBP-Jκ, NF-κB, and STAT, are involved in this expression, but the underlying mechanism is unclear. Here, we identified binding sites for PAX5, AP-2, and EBF in the proximal LMP1 promoter (ED-L1p). We first confirmed the significance of PU.1 and POU domain transcription factor binding for activation of the promoter in latency III. We then focused on the transcription factors AP-2 and early B cell factor (EBF). Interestingly, among the three AP-2-binding sites in the LMP1 promoter, two motifs were also bound by EBF. Overexpression, knockdown, and mutagenesis in the context of the viral genome indicated that AP-2 plays an important role in LMP1 expression in latency II in epithelial cells. In latency III B cells, on the other hand, the B cell-specific transcription factor EBF binds to the ED-L1p and activates LMP1 transcription from the promoter.IMPORTANCEEpstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBV-related malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma. Its expression is largely dependent on the cell type or condition, and some transcription factors have been implicated in its regulation. However, these previous reports evaluated the significance of specific factors mostly by reporter assay. In this study, we prepared point-mutated EBV at the binding sites of such transcription factors and confirmed the importance of AP-2, EBF, PU.1, and POU domain factors. Our results will provide insight into the transcriptional regulation of the major oncogene LMP1.
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Lu, Hanxin, Cynthia A. Pise-Masison, Terace M. Fletcher, R. Louis Schiltz, Akhilesh K. Nagaich, Michael Radonovich, Gordon Hager, Philip A. Cole, and John N. Brady. "Acetylation of Nucleosomal Histones by p300 Facilitates Transcription from Tax-Responsive Human T-Cell Leukemia Virus Type 1 Chromatin Template." Molecular and Cellular Biology 22, no. 13 (July 1, 2002): 4450–62. http://dx.doi.org/10.1128/mcb.22.13.4450-4462.2002.
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ABSTRACT Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. One key property of the coactivators is the presence of histone acetyltransferase (HAT) activity, which enables p300/CBP to modify nucleosome structure. The data presented in this manuscript demonstrate that full-length p300 and CBP facilitate transcription of a reconstituted chromatin template in the presence of Tax and CREB. The ability of p300 and CBP to activate transcription from the chromatin template is dependent upon the HAT activity. Moreover, the coactivator HAT activity must be tethered to the template by Tax and CREB, since a p300 mutant that fails to interact with Tax did not facilitate transcription or acetylate histones. p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5′ proximal regions of the template. Nucleosome acetylation is accompanied by an increase in the level of binding of RNA polymerase II transcription factor TFIID and RNA polymerase II to the promoter. Interestingly, we found distinct transcriptional activities between CBP and p300. CBP, but not p300, possesses an N-terminal activation domain which directly activates Tax-mediated HTLV-1 transcription from a naked DNA template. Finally, using the chromatin immunoprecipitation assay, we provide the first direct experimental evidence that p300 and CBP are associated with the HTLV-1 long terminal repeat in vivo.
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Finlay, David K., Ella Rosenzweig, Linda V. Sinclair, Carmen Feijoo-Carnero, Jens L. Hukelmann, Julia Rolf, Andrey A. Panteleyev, Klaus Okkenhaug, and Doreen A. Cantrell. "PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells." Journal of Experimental Medicine 209, no. 13 (November 26, 2012): 2441–53. http://dx.doi.org/10.1084/jem.20112607.
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mTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8+ cytolytic T cell (CTL) fate. In some cell systems, mTORC1 couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control of glucose uptake and glycolysis. However, PI3K–Akt-independent mechanisms control glucose metabolism in CD8+ T cells, and the role of mTORC1 has not been explored. The present study now demonstrates that mTORC1 activity in CD8+ T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8+ T cells. We also show that PI3K- and Akt-independent pathways mediated by mTORC1 regulate the expression of HIF1 (hypoxia-inducible factor 1) transcription factor complex. This mTORC1–HIF1 pathway is required to sustain glucose metabolism and glycolysis in effector CTLs and strikingly functions to couple mTORC1 to a diverse transcriptional program that controls expression of glucose transporters, multiple rate-limiting glycolytic enzymes, cytolytic effector molecules, and essential chemokine and adhesion receptors that regulate T cell trafficking. These data reveal a fundamental mechanism linking nutrient and oxygen sensing to transcriptional control of CD8+ T cell differentiation.
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Ku, Sebastian C. Y., Jialing Lee, Joanne Lau, Meera Gurumurthy, Raymond Ng, Siew Hui Lwa, Joseph Lee, Zachary Klase, Fatah Kashanchi, and Sheng-Hao Chao. "XBP-1, a Novel Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Binding Protein, Activates HTLV-1 Basal and Tax-Activated Transcription." Journal of Virology 82, no. 9 (February 20, 2008): 4343–53. http://dx.doi.org/10.1128/jvi.02054-07.
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ABSTRACT X-box binding protein 1 (XBP-1), a basic leucine zipper transcription factor, plays a key role in the cellular unfolded protein response (UPR). There are two XBP-1 isoforms in cells, spliced XBP-1S and unspliced XBP-1U. XBP-1U has been shown to bind to the 21-bp Tax-responsive element of the human T-lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) in vitro and transactivate HTLV-1 transcription. Here we identify XBP-1S as a transcription activator of HTLV-1. Compared to XBP-1U, XBP-1S demonstrates stronger activating effects on both basal and Tax-activated HTLV-1 transcription in cells. Our results show that both XBP-1S and XBP-1U interact with Tax and bind to the HTLV-1 LTR in vivo. In addition, elevated mRNA levels of the gene for XBP-1 and several UPR genes were detected in the HTLV-1-infected C10/MJ and MT2 T-cell lines, suggesting that HTLV-1 infection may trigger the UPR in host cells. We also identify Tax as a positive regulator of the expression of the gene for XBP-1. Activation of the UPR by tunicamycin showed no effect on the HTLV-1 LTR, suggesting that HTLV-1 transcription is specifically regulated by XBP-1. Collectively, our study demonstrates a novel host-virus interaction between a cellular factor XBP-1 and transcriptional regulation of HTLV-1.
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Barnitz, R. Anthony, Makoto Kurachi, Madeleine E. Lemieux, Nir Yosef, Michael A. DiIorio, Kathleen B. Yates, Jernej Godec, et al. "The Transcription Factor BATF Controls CD8+ T Cell Effector Differentiation." Blood 122, no. 21 (November 15, 2013): 189. http://dx.doi.org/10.1182/blood.v122.21.189.189.
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Abstract Following activation by antigen, costimulation, and inflammation, naïve CD8+ T cells initiate a program of clonal expansion and differentiation resulting in wide-spread changes in expression of genes involved in cell-cycle, metabolism, effector function, apoptosis, and homing. Although, several key transcription factors (TFs) have been shown to be important in effector CD8+ T cell differentiation, the precise transcriptional regulation of this differentiation program remains poorly understood. The AP-1 family member BATF plays an important role in regulating differentiation and function in CD4+ Th17 cells, CD4+ follicular helper T cells, and in Ig class switching in B cells. We now show that BATF is also required for effector CD8+ T cell differentiation and regulates a core program of genes involved in effector differentiation. We found that BATF expression is rapidly up-regulated during effector CD8+ T cell differentiation in the mouse model of lymphocytic choriomeningitis virus (LCMV) infection. To examine the role of BATF in effector differentiation, we studied congenically distinct wild type (WT) and BATF knockout (KO) naïve P14 TCR transgenic CD8+ T cells co- transferred into a WT host. Upon infection, the BATF KO cells exhibited a profound, cell-intrinsic defect in effector CD8+ T cell differentiation, with a ∼400-fold decrease in peak number of effector cells. BATF KO effectors showed sustained activation and increased cell death by the mid-expansion phase of the immune response. To address the question of how loss of BATF causes such a severely diminished antigen-specific response, we profiled the binding sites of BATF throughout the genome by chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) in primary CD8+ effector cells. We found that BATF bound to regulatory regions in many genes critical for effector differentiation, including transcription factors (e.g. Tbx21, Eomes, Prdm1), genes involved in cytokine signaling (e.g. Il12rb2, Il2ra), homing (e.g. Sell, Selp, Ccr9), effector function (e.g. Gzmb, Ifng, Il2), apoptosis (e.g. Bcl2, Bcl2l1, Mcl1), and T cell activation (e.g. Ctla4, Cd247, Tnfrsf4), suggesting a major role for BATF in effector CD8+ T cell differentiation. Indeed, we found that genes bound by BATF were highly significantly overrepresented among genes that changed as a result of naïve CD8+ T cells differentiating into effectors in vivo (P = 10-27). Comparison of gene expression in in vitro WT and BATF KO effectors confirmed that BATF bound genes were perturbed by BATF loss of function. Analysis of the kinetics of gene expression during the first 72 hours of effector differentiation showed that loss of BATF perturbed the temporal sequence of expression of critical transcription factors, such as T-bet and Eomes, and resulted in inappropriately early cytokine expression. This suggests that BATF may be required to coordinate the earliest events in CD8+ T cell effector differentiation. To test this hypothesis, we used in vivo CFSE tracking to follow the early CD8+ T cell response during LCMV infection. We found that while BATF KO CD8+ T cells initiate cell division, there was a dramatic collapse in the ability to sustain proliferation and differentiation as early as day 3 post-infection. These results indicate that BATF ensures the orderly progression of a program of genes required by effector cells, restraining the expression of some and promoting the expression of others. More broadly, our results suggest that BATF may provide a common regulatory infrastructure for the development of effector cells in all T cell lineages. Disclosures: Wherry: Genentech: Patents & Royalties.
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Ding, Wei, Seung-Jae Kim, Amrithraj M. Nair, Bindhu Michael, Kathleen Boris-Lawrie, Adam Tripp, Gerold Feuer, and Michael D. Lairmore. "Human T-Cell Lymphotropic Virus Type 1 p12I Enhances Interleukin-2 Production during T-Cell Activation." Journal of Virology 77, no. 20 (October 15, 2003): 11027–39. http://dx.doi.org/10.1128/jvi.77.20.11027-11039.2003.
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ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL) and a variety of lymphoproliferative disorders. The early virus-cell interactions that determine a productive infection remain unclear. However, it is well recognized that T-cell activation is required for effective retroviral integration into the host cell genome and subsequent viral replication. The HTLV-1 pX open reading frame I encoding protein, p12I, is critical for the virus to establish persistent infection in vivo and for infection in quiescent primary lymphocytes in vitro. p12I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus, increases intracellular calcium and activates nuclear factor of activated T cells (NFAT)-mediated transcription. To clarify the function of p12I, we tested the production of IL-2 from Jurkat T cells and peripheral blood mononuclear cells (PBMC) expressing p12I. Lentiviral vector expressed p12I in Jurkat T cells enhanced interleukin-2 (IL-2) production in a calcium pathway-dependent manner during T-cell receptor (TCR) stimulation. Expression of p12I also induced higher NFAT-mediated reporter gene activities during TCR stimulation in Jurkat T cells. In contrast, p12 expression in PBMC elicited increased IL-2 production in the presence of phorbal ester stimulation, but not during TCR stimulation. Finally, the requirement of ER localization for p12I-mediated NFAT activation was demonstrated and two positive regions and two negative regions in p12I were identified for the activation of this transcription factor by using p12I truncation mutants. These results are the first to indicate that HTLV-1, an etiologic agent associated with lymphoproliferative diseases, uses a conserved accessory protein to induce T-cell activation, an antecedent to efficient viral infection.