This group works on gene regulation in the immune system. Our focus has been to elucidate the role of two transcription factors, RXRbeta and ICSBP that we have isolated previously. RXRbeta is a member of the nuclear hormone receptor superfamily and by heterodimerizing with retinoic acid receptor (RAR), it regulates retinoic acid (RA) responsive genes. ICSBP is a member of the interferon regulatory factor (IRF) family and is involved in viral/interferon (IFN) mediated gene regulation. To further study the role of ICSBF and other members of the IRF family in the immune system, a dominant negative ICSBP has been constructed which has only the DNA binding domain (DBD) and lacks a large C-terminal domain. This construct was stably transfected into a human monocytic cell line U937 cells, and a number of clones expressing the DBD have been established. The DBD clones exhibited altered infectivity by several viruses: they were refractory to infection by vaccinia virus, ectromeria virus as well as human immunodeficiency virus-1. In contrast, control clones and those expressing the intact ICSBP were strongly infected by these viruses. The DBD clones were, however, infected by vesicular stomatitis virus (VSV) as efficiently as control clones. But, IFN pretreatment known to confer protection against VSV, completely failed to protect DBD clones. As expected control clones and those ex pressing intact ICSBP were fully protected from VSV infection by IFNs. These results indicate that some viruses depends on the IRF proteins for their infection and growth in host cells. By genomic footprinting analysis we have studied binding of RXR heterodimers to the promoter of an RA responsive gene (RARbeta) in P19 EC cells. We show that the RA responsive element (RARE) in the RARbeta gene is not occupied prior to RA treatment, but becomes occupied within 1 h of RA treatment, without requiring new protein synthesis. This in vivo occupancy accompanied factor binding to other elements in the promoter. The occupancy at all sites was rapidly reversed when PA was withdrawn from culture medium. On the other hand, P19 cells expressing a dominant negative RXRbeta that blocks binding of endogenous RAR/RXR heterodimers to the RARE, did not exhibit occupancy at all elements in the promoter. Our observations underscore the significance of ligand for receptor/DNA interaction in vivo and demonstrate the presence of a hierarchy in factor binding processes.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1994
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Indirect Cost
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United States
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Umehara, Takashi; Nakamura, Yoshihiro; Wakamori, Masatoshi et al. (2010) Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2. FEBS Lett 584:3901-8
Kubota, Toru; Matsuoka, Mayumi; Chang, Tsung-Hsien et al. (2009) Ebolavirus VP35 interacts with the cytoplasmic dynein light chain 8. J Virol 83:6952-6
Chang, Tsung-Hsien; Kubota, Toru; Matsuoka, Mayumi et al. (2009) Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog 5:e1000493
Tailor, Prafullakumar; Tamura, Tomohiko; Kong, Hee Jeong et al. (2007) The feedback phase of type I interferon induction in dendritic cells requires interferon regulatory factor 8. Immunity 27:228-39
Cho, Won-Kyung; Zhou, Meisheng; Jang, Moon Kyoo et al. (2007) Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J Virol 81:11179-86
Gabriele, Lucia; Ozato, Keiko (2007) The role of the interferon regulatory factor (IRF) family in dendritic cell development and function. Cytokine Growth Factor Rev 18:503-10
Ozato, Keiko; Tailor, Prafullakumar; Kubota, Toru (2007) The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem 282:20065-9
Kong, Hee Jeong; Anderson, D Eric; Lee, Chang Hoon et al. (2007) Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol 179:26-30
Dror, Natalie; Rave-Harel, Naama; Burchert, Andreas et al. (2007) Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells. J Biol Chem 282:5633-40
Ozato, Keiko; Uno, Kazuko; Iwakura, Yoichiro (2007) Another road to interferon: Yasuichi Nagano's journey. J Interferon Cytokine Res 27:349-52

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