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.