The transin cDNA was originally cloned by the P.J. as an oncogene-inducible gene. Subsequent studies have revealed that transin is the rat homologue of the extracellular matrix-degrading metalloproteinase also referred to as stromelysin, proteoglycanase, procollagenase activator, and matrix metalloproteinase-3 (MMP-3). We have demonstrated a strong correlation between the expression of transin and the progression of tumors in a mouse skin carcinogenesis model system. We propose to extend these studies to determine if the expression of active transin plays a causal role in tumor progression, invasion, and metastasis. Several approaches, including in situ localization of transin RNA and protein in metastatic tumors, in vivo grafting experiments, and transgenic mice are proposed to test this hypothesis. In addition, we have identified both cis- and transacting elements that are involved in growth factor and oncogene regulation of transin gene expression. We propose to extend these studies to further delineate the pathways used by the oncogenes Ha-ras and v-src to stimulate transin transcription, and the role of various protein kinase C isotypes in induction of transin gene expression. The multiplicity of pathways that can be utilized to stimulate transin gene expression provides an ideal model system to examine possible interactions between these transcriptional pathways, and how this may affect the regulation of a biologically-relevant gene. The ultimate goal of these studies is to understand the molecular mechanism by which the expression of transin is triggered during tumor progression so that rational approaches can be taken to interfere with tumor invasion and metastasis.
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