Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease

Abstract

Activator protein 1 (AP-1) (Fos/Jun) is a transcriptional regulator composed of members of the Fos and Jun families of DNA binding proteins. The functions of AP-1 were initially studied in mouse development as well as in the whole organism through conventional transgenic approaches, but also by gene targeting using knockout strategies. The importance of AP-1 proteins in disease pathways including the inflammatory response became fully apparent through conditional mutagenesis in mice, in particular when employing gene inactivation in a tissue-specific and inducible fashion. Besides the well-documented roles of Fos and Jun proteins in oncogenesis, where these genes can function both as tumor promoters or tumor suppressors, AP-1 proteins are being recognized as regulators of bone and immune cells, a research area termed osteoimmunology. In the present article, we review recent data regarding the functions of AP-1 as a regulator of cytokine expression and an important modulator in inflammatory diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis. These new data provide a better molecular understanding of disease pathways and should pave the road for the discovery of new targets for therapeutic applications. IntroductionThe transcription factor activator protein 1 (AP-1) consists of dimers composed of members of the Jun, Fos and activating transcription factor protein families. In contrast to the Fos proteins (Fos, FosB, Fra-1 and Fra-2), which can only heterodimerize with members of the Jun family, Jun family members (Jun, JunB and JunD) can homodimerize and heterodimerize with Fos members [1]. In addition, some members of the activating transcription factor and cAMP response elementbinding protein families also dimerize with the core members of the AP-1 family to regulate a broad variety of genes [2] by binding to their promoter and enhancer regions (Figure 1).Although members of the Jun and Fos families share a high degree of structural homology, the individual AP-1 dimers exert significant differences in their DNA binding affinity and their capability to activate or suppress gene expression [3]. AP-1 converts extracellular signals of evolutionary conserved signaling pathways like mitogen-activated protein kinase, transforming growth factor beta and Wnt into changes in the expression of specific target genes that harbor AP-1 binding sites. Growth factors, neurotransmitters, polypeptide hormones, bacterial and viral infections as well as a variety of physical and chemical stresses employ AP-1 to translate external stimuli both into short-term and long-term changes of gene expression. These stimuli activate mitogen-activated protein kinase cascades that enhance AP-1 activity; for example, through phosphorylation of distinct substrates [4]. Activator protein 1 functions in miceMany important insights regarding the specific functions of AP-1 proteins in development and disease have been obtained from genetically modified mice and the cells derived thereof (Table 1) [1,2]. In the following s...

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

“…Jun proteins were recognized as important regulators of cytokine expression and immune response (13). The function of Jun proteins within the AP-1 complex crucially depends on the cellular context.…”

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

“…JNKs can activate Jun proteins. 34 In the present study, we found elevated JNKs and c-Jun activities in the skin of Ikka À/À mice, and we found that the transgenic IKKa or reduced EGFR repressed these activities in an IKKa dosedependent manner. Thus, the enhanced JNK and c-Jun activities may contribute to the epidermal hyperplasia, skin inflammation, and tumorigenesis in IKKa-deficient mice.…”

“…33,34 The EGFR/HB-EGF pathway is important for the AP-1 pathway in maintaining skin homeostasis. Jun/AP-1 proteins also regulate the expression of cytokines, such as IL-6 and TNFa.…”

The SWI/SNF Chromatin-remodeling Complex Modulates Peripheral T Cell Activation and Proliferation by Controlling AP-1 Expression

“…AP-1 is a dimer of the Fos and/or Jun proteins, and it regulates the expression of a broad variety of genes (12). The target genes of AP-1 play important roles in proliferation, differentiation, and apoptosis (13). The expression of AP-1 is tightly linked to mitogenic stimulation, and this finding suggests that AP-1 performs essential functions in cell proliferation.…”

“…INK4A (13). AP-1 is essential for the expression of the IL-2 gene in response to TCR/CD28 stimulation; therefore, AP-1 is intimately involved in T cell proliferation (15,16).…”