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This post must therefore be hereby marked advertisement in accordance with 18 USC section 1734 solely to indicate this fact

This post must therefore be hereby marked advertisement in accordance with 18 USC section 1734 solely to indicate this fact. Footnotes E-MAIL hc.eginu.enicedem@htieR.retlaW; FAX 41-22-7025702.. regulatory and gene-specific transcriptional cofactor. expression, constitutive and inducible, are generally acknowledged (Benoist and Mathis 1990; Glimcher and Kara 1992; Ting and Baldwin 1993; Mach et al. 1996; Boss 1997). Constitutive expression is largely restricted to specialized Raphin1 acetate cells of the immune system, including thymic epithelial cells and professional APC such as B cells, macrophages, and dendritic cells. The majority of other cell types lack MHC-II molecules, but can be induced to express them by exposure to various inducing brokers, of which the most potent and well known is usually interferon-. Both modes of expression are controlled primarily at the level of transcription. The major transcriptional control element is usually a short 150-bp regulatory module that has been conserved in the promoter proximal regions of all MHC-II, genes (Benoist and Mathis 1990; Glimcher and Kara 1992; Ting and Baldwin 1993; Mach et al. 1996; Boss 1997). This regulatory module consists of four genes are constitutively expressed in virtually all nucleated cells, and their transcription is usually predominantly driven by promoters. NF-Y (CBF, CP1) is usually a well characterized, ubiquitous CCAAT-binding protein that associates with a wide variety of eukaryotic RNA Pol II promoters (Maity and De Crombrugghe 1998; Mantovani 1999). The X2-binding protein (X2BP) belongs to a large family of bZip transcription factors. A number of these factors are capable of binding to the X2 boxes of MHC-II promoters Raphin1 acetate in vitro (Benoist and Mathis 1990; Mach et al. 1996; Boss 1997) and the precise Rabbit Polyclonal to C-RAF identity of X2BP has for long remained unclear. At least one member of the bZip family, the cAMP responsive element-binding protein 1 (CREB-1), may be considered as a bona fide candidate for X2BP, because chromatin immunoprecipitation experiments demonstrated that it associates with MHC-II promoters in vivo (Moreno et al. 1999). CREB-1 also activated transcription of a reporter gene in an X2-dependent manner (Moreno et al. 1999). Binding of RFX, X2BP, and NF-Y to the promoter DNA is usually highly cooperative and results in the formation of a remarkably stable higher-order nucleoprotein complex (Reith et al. 1994a,b; Louis-Plence et al. 1997) that can be regarded as the MHC-II enhanceosome (Thanos and Maniatis 1995). In the absence of RFX, the enhanceosome cannot form such that MHC-II promoters remain unoccupied in vivo (Kara and Glimcher 1991, 1993). Enhanceosome assembly is essential but not sufficient for MHC-II expression, which ultimately depends on CIITA (Steimle et al. 1993), a highly regulated grasp control factor that determines the level, cell type specificity, inducibility, and extinction of MHC-II expression (Steimle et al. 1993, 1994; Silacci et al. 1994; Mach et al. 1996; Boss 1997; Otten et al. 1998). The complex control of CIITA transcription is in its turn achieved by the differential activation of multiple alternate promoters (Muhlethaler-Mottet et al. 1997). The biological role of CIITA as a grasp controller of MHC-II genes has now been firmly established. On the other hand, despite 6 years of research, relatively little has been learned about its mode of action. CIITA does not bind to DNA (Steimle et al. 1993). Instead, it is believed to function as a transcriptional coactivator that is recruited to MHC-II promoters by interactions with promoter-bound factors (Riley et al. 1995; Zhou and Glimcher 1995; Scholl et al. 1997; Brown et al. 1998). However, data supporting this hypothetical working model has remained disappointingly indirect. Evidence consistent with the model was provided by studies suggesting that CIITA contains amino-terminal acidic and proline/serine/threonine-rich transcription activation domains that can contact general transcription factors and coactivators (Riley et al. 1995; Zhou and Glimcher 1995; Bontron et al. 1997b; Chin et Raphin1 acetate al. 1997; Mahanta et al. 1997; Brown et.