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Fos-Jun Interactions That Mediate Transcription Regulatory Speci®City

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Fos-Jun Interactions That Mediate Transcription Regulatory Speci®City Oncogene (2001) 20, 2438 ± 2452 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Close encounters of many kinds: Fos-Jun interactions that mediate transcription regulatory speci®city Yurii Chinenov1 and Tom K Kerppola*,1 1Howard Hughes Medical Institute, University of Michigan Medical School Ann Arbor, Michigan, MI 48109-0650, USA Fos and Jun family proteins regulate the expression of a Wang et al., 1992). However, only a few of the genes myriad of genes in a variety of tissues and cell types. that mediate the essential functions of speci®c Fos and This functional versatility emerges from their interac- Jun family members have been identi®ed (Bakin and tions with related bZIP proteins and with structurally Curran, 1999; Fu et al., 2000) unrelated transcription factors. These interactions at Fos and Jun family proteins function as dimeric composite regulatory elements produce nucleoprotein transcription factors that bind to AP-1 regulatory complexes with high sequence-speci®city and regulatory elements in the promoter and enhancer regions of selectivity. Several general principles including binding numerous mammalian genes (Curran and Franza, cooperativity and conformational adaptability have 1988). Jun proteins form both homodimers and emerged from studies of regulatory complexes containing heterodimers with Fos proteins, whereas Fos proteins Fos-Jun family proteins. The structural properties of do not form homodimers and require heterodimeriza- Fos-Jun family proteins including opposite orientations tion to bind DNA. The DNA-binding and dimerization of heterodimer binding and the ability to bend DNA can domains among dierent family members are highly contribute to the assembly and functions of such conserved and dierent members of the Fos and Jun complexes. The cooperative recruitment of transcription families have similar DNA-binding and dimerization factors, coactivators and chromatin remodeling factors to speci®cities. promoter and enhancer regions generates multiprotein In vitro, dimers formed by Fos and Jun bind with the transcription regulatory complexes with cell- and highest anity to an asymmetric heptanucleotide stimulus-speci®c transcriptional activities. The gene- recognition sequence TGA(C/G)TCA (AP-1) and with speci®c architecture of these complexes can mediate the slightly lower anity, to a symmetric octanucleotide selective control of transcriptional activity. Oncogene TGACGTCA (CRE) (Nakabeppu et al., 1988; (2001) 20, 2438 ± 2452. Rauscher et al., 1988). The AP-1 site is a ubiquitous regulatory element that is found in a wide range of Keywords: transcription factor cooperativity; nucleo- promoter and enhancer regions. Since the AP-1 site protein complex architecture; transcriptional synergy; and variants thereof occur with a high frequency in the composite regulatory elements; orientation of hetero- genome, it is unlikely that Fos-Jun family proteins dimer binding regulate all genes that contain AP-1 recognition sequences. Conversely, many genes that are bona ®de regulatory targets of Fos-Jun family proteins do not contain consensus AP-1 recognition sequences within Regulatory functions of Fos and Jun family transcription their control regions. In natural promoter and factors enhancer regions, the sequences of AP-1 regulatory elements often deviate from the optimal recognition Members of the Fos and Jun protein families (Curran sequence. This variation in recognition sequences may and Teich, 1982; Maki et al., 1987) participate in the contribute to the dierential functions of dierent Fos- regulation of a variety of cellular processes including Jun family dimers at various regulatory elements cell proliferation, dierentiation, apoptosis and onco- (McBride and Nemer, 1998) The weaker binding genesis. Members of this family (Fos, Fra-1, Fra-2, anities of Fos-Jun family members at these non- FosB, Jun, JunB and JunD) are widely expressed in consensus recognition sites may also impose a require- diverse cell types and tissues. The results of gene ment for interactions with other transcription factors. knockout experiments indicate that Fos and Jun family The functions of Fos-Jun family proteins depend on proteins have both overlapping functions as well as the speci®c cell type in which they are expressed. Only unique roles that cannot be compensated for by other a small subset of all potential regulatory targets is family members (Grigoriadis et al., 1994; Hilberg et al., controlled by Fos-Jun family proteins in any particular 1993; Johnson et al., 1992, 1993; Schorpp-Kistner et cell type. The activities and regulatory targets of Fos- al., 1999; Schreiber et al., 2000; Thepot et al., 2000; Jun family proteins are also aected by the speci®c signals that elicit their expression. Thus, the functions of Fos-Jun family proteins must be mediated by *Correspondence: TK Kerppola mechanisms that depend on the cellular context in Protein-protein interactions of Fos-Jun family members Y Chinenov and TK Kerppola 2439 which they are expressed. Several mechanisms that may progression of dierent homo- and heterodimeric Fos contribute to the cell type speci®city of Fos-Jun family and Jun family protein complexes is thought to proteins can be envisioned. These include dierential contribute to the time-dependent induction of dierent post-translational modi®cations, selective dimerization early and late genes in dierent cell types activated by between dierent family members and interactions with dierent stimuli. other regulatory protein. The ®rst two mechanisms modulate the activities of Fos-Jun proteins, but they have mostly indirect eects on selection of the genes Interaction between Fos-Jun proteins and other that are regulated by Fos-Jun family proteins in a bZIP family proteins particular cell type. Interactions with other transcrip- tion factors can modify the regulatory speci®cities of Fos-Jun family proteins are members of a large group Fos-Jun family proteins in a cell or tissue speci®c of transcription factors (the bZIP family) containing a manner. Thus, Fos-Jun proteins have to be considered highly conserved basic region involved in DNA binding in the broad context of dynamically changing protein- and a heptad repeat of leucine residues, the leucine protein interactions on and o DNA. zipper, required for dimerization (Landschulz et al., Interactions between various Fos-Jun family members 1988). All bZIP proteins form dimeric complexes and more than 50 dierent proteins have been reported through the leucine zipper that juxtapose the two basic (Table 1). Fos-Jun interacting proteins can be sub- regions to form a contiguous DNA-contact interface in divided into four groups: (1) structurally related basic which each monomer interacts with the major groove region ± leucine zipper proteins; (2) unrelated DNA of one half-site (Ellenberger et al., 1992; Fujii et al., binding proteins; (3) transcriptional coactivators that do 2000; Glover and Harrison, 1995; Schumacher et al., not bind DNA directly; and (4) structural components 2000). Since members of dierent bZIP protein of the nucleus. In many cases, either the functional subfamilies exhibit distinct DNA binding speci®cities, signi®cance or the structural basis of the interaction dimerization between Fos-Jun and other bZIP proteins remains under investigation. Nevertheless, it is clear that expands the repertoire of binding sites for Fos-Jun interactions among many structurally divergent protein family proteins to include sequences composed of families can contribute to the functional speci®city of dierent half-sites. Diversi®cation of binding speci®- Fos-Jun family proteins. In this review, we focus on cities through the formation of cross-family dimers is a interactions between Fos-Jun family members and other common characteristic of bZIP proteins. Cross-family DNA binding proteins that can in¯uence the regulatory dimerization between Fos-Jun proteins and various speci®cities of Fos-Jun family proteins. members of the ATF, C/EBP, Maf and NF-E2 (CNC) proteins (Table 1) has been observed. Interactions among Fos and Jun family members ATF proteins The repertoire of Fos-Jun proteins in a given cell is Several members of the ATF group of bZIP proteins subject to changes in response to various extracellular form heterodimers with Fos and Jun family proteins. stimuli. Through dimerization mediated by the leucine The ATF2 and ATF3 proteins preferentially interact zipper, the seven Fos-Jun family members can form 18 with CRE (TGACGTCA) rather than AP-1 sites. dierent homo and heterodimers. The number of Heterodimerization between Fos-Jun and these pro- detectable Fos-Jun dimers varies among dierent cell teins can target Fos-Jun proteins to CRE-like sites (Hai types (Kovary and Bravo, 1991; Lallemand et al., 1997; and Curran, 1991). Many of the promoters that are McCabe et al., 1995; Sonnenberg et al., 1989). controlled by heterodimers formed by ATF2 with Fos- Quiescent ®broblasts contain mainly homodimers Jun family proteins contain asymmetric binding sites formed by Jun and JunD, but following serum (TTACCTCA in the Jun promoter, TGACATAG in stimulation, heterodimers formed ®rst by Fos and the b-interferon promoter and CTCAGTCA in the FosB and later by Fra-1 with Jun and JunB become adenovirus E2A promoter). Neither Fos-Jun nor Jun- the predominant AP-1 binding proteins (Kovary and Jun bind eciently to these sites (Du et al., 1993; van Bravo, 1992; Lallemand et al., 1997). In exponentially Dam et al., 1993). Since Jun and ATF proteins
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