VARIOUS MODES OF GENE-REGULATION BY NUCLEAR RECEPTORS FOR STEROID ANDTHYROID-HORMONES

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in respo nse to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional. control of jun and fos ge ne expression determines the amount and composition of the AP-1 comple x. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post tr anslational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosph orylation reverses this inhibition. Phosphorylation of cJun on sites w ithin the N-terminal activation domain increases its ability to activa te transcription. The protein kinase phosphorylating these sites is st imulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nucle ar receptor family and is relevant for the pathophysiology of rheumato id arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells, macrophages and synoviocytes as a response to se cretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene p lays a major role in T cell activation, another AP-1 target gene encod es an enzyme, collagenase, responsible for destruction of bone and ten don. Glucocorticoids and retinoids are capable of repressing expressio n of both genes as well as other AP-1 target genes. We found that the glucocorticoid and retinoic acid receptors interact with cJun and cFos to inhibit their ability to activate AP-1 target genes.