The long-term objective of this research is to define alterations in cell-extracellular matrix (ECM) interactions that play a role in the development of cancer. Metastasis of epithelial tumors, such as breast carcinomas, occurs when the cells are no longer constrained by the basement membrane that separates them from the underlying stroma. Matrix metalloproteinases (MMPs) are implicated in degradation of the basement membrane during cancer invasion and metastasis. Their activity is controlled, in part, by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We have recently described a new member of the TIMP family, TIMP-1 and TIMP-2, most notably in its ECM localization and its ability to promote cell transformation. Based on our studies of TIMP-3 expression in cultured cells and in vivo, we propose the following hypothesis: TIMP-3 is an onco-fetal protein; although it is synthesized in some adult tissues, it is predominantly expressed during embryogenesis and is developmentally regulated. Recently, a tertiary structure of TIMP-2 has been solved by NMR. We have obtained these coordinates and wish to model TIMP-3 using sequence homology. The two proteins are over 60% homologous. MIDAS can aid us in determining possible sites for the inhibitory interaction or the cytokine signaling.
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