Since the discovery of its first member more than two decades ago, the AP-1 transcription complex has evolved into a paradigm for the transcription factors. The AP-1 regulate many aspects of cell physiology in response to growth factor signals and environmental insults, acting as master regulators of cell activities. c-Jun, the most extensively studied AP-1 protein, is involved in numerous cell functions, such as proliferation, apoptosis, survival, tumorigenesis,and tissue morphogenesis. Most of these activities rely on c-Jun function as a transcription factor, but its specificity in target gene selection and the intensity of its activity appear to be decided in a cell type or context-dependent manner. This article will focus on the mechanisms involved in c-Jun regulation, target gene expression and physiological functions, and will address the complex nature of this transcription factor.

The AP-1 Transcription Complex

AP-1 is a collective term for dimmers formed by proteins of the Jun (c-Jun, JunB and JunD), Fos (c-Fos, FosB, Fral and Fra2), activating transcription factor (ATF) (ATF2, ATF3/LRF1, B-ATF, JDP1 and JDP2) and musculoaponeurotic fibrosarcoma (MAF) (c-Maf, MafB, MafA, MafG/F/K and Nrl) families (Angel and Karin, 1991; Hai et al., 1988). These are structurally similar and functionally related basic leucine zipper

(bZIP) proteins, forming homo- and/or hetero-dimers through the heptad repeat of leucine residues. Dimerization is essential for AP-1 function, because it brings together the two basic regions, constituting a contiguous DNA-contact interface that interacts with specific sequences in the major groove of one half-site on DNA (Ellenberger et al., 1992; Schumacher et al., 2000). Binding to the target sites allows the AP-1 to activate or repress genes in the nucleus and to function as fundamental transcription regulators.

This seemingly simple regulatory scheme, however, is entangled due to the complexity involved in the structure and regulation of each AP-1 protein. The relative abundance of a given AP-1 component in the cell is largely determined by its living environment, which controls its promoter activity, mRNA turnover and protein stability. Once expressed, the AP-1 component selectively binds to other available AP-1 proteins in its surroundings to form various protein dimers. The Jun proteins form homo- or hetero-dimers with members of Fos and ATF families. ATF, but not Fos, also form stable homodimers. While c-Maf and Nrl heterodimerize with c-Jun and c-Fos, other Maf-related proteins, including MafB, MafF, MafG and MafK, heterodimerizes with only Fos, but not Jun (Landschulz et al., 1988). Each AP-1 dimer may vary in affinity for binding to DNA with the consensus 5'-TGA(C/G)TCA-3' sequence. The most well known AP-1 binding sites are the phorbol 12 O-tetradecanoate-13-acetate (TPA)-responsive element (TRE, 5'-TGAG/CTCA-3') and the cAMP-responsive element (CRE, 5'-TGACGTCA-3'), while some dimers possess weak affinity for non-consensus sequences deviated from the traditional AP-1 sites. The Jun/ATF

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dimers bind to the CRE sequence, Jun/Fos binds to TRE, while the Jun/Maf binds to both. The AP-1 dimers regulate diverse gene expression through binding to the AP-1 sites that are widely spread in gene promoter or enhancer regions (Karin et al., 1997).

The rapid induction of AP-1 activity by a vast number of factors, including growth factors, cytokines, neurotransmitters, oncoproteins, cell-matrix interactions and a variety of physiological and chemical stresses is mainly attributed to the post-translational modification that alters the activities of AP-1 proteins in dimerization, DNA-binding and transactivation. This property allows the AP-1 to convert extracellular signals into gene expression events, which in turn control a plethora of cellular processes, including proliferation, survival, apoptosis and transformation. Although the complexity of AP-1 regulation and function is well appreciated, its functions rely largely on the specific roles for individual AP-1 protein.

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