Cell-cell and cell-extracellular matrix interactions regulate virtually all aspects of differentiation, organ development, tumor invasion and inflammation. Although there are several families of adhesive receptors and corresponding ligands, one of the major families, the integrins is critically involved in monocyte/macrophage function. Very little is known of how specific integrins signal cellular responses, even though they regulate very specific patterns of cellular differentiation. We are interested in identifying how integrins associate with the cytoskeleton and how these interactions regulate the transcriptional machinery of the cell. We have identified several novel genes, one an inhibitor of the transcription factor NF-kappaB, IkappaB, and a zinc finger gene, MAD-6, that functions following adhesion to collagen. IkappaB is likely to associate with integral membrane components, in particular the cytoskeleton. It therefore represents an excellent target for studying the relationship between integrins, which activate the gene, and nuclear transcription. The MAD-6 gene modifies fibroblast growth and differentiation patterns. We therefore have a transcription factor gene that is selectively induced by a matrix-cell interaction. Our plan is to analyze the cellular binding sites of the IkappaB gene and to define the cytoskeletal interactions and to transfect cell lines with this and mutant genes to study the influence of this gene on inflammation and host responses. The MAD-6 gene will serve as a model for investigating the transcriptional response elements of a collagen response gene and we will define the role that particular integrins have in selectively transcribing this important regulator of differentiation. These studies should lead to an understanding of how integrins regulate transcription thereby leading to novel approaches to regulating tumor invasiveness and chronic inflammation.
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