Bond, M., Murphy, G., Bennett, M., Amour, A., Knauper, V., Newby, A., and Baker, A. (2000) Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus - Metalloproteinase inhibition is associated with proapoptotic activity. Journal of Biological Chemistry, 275 (52). pp. 41358-41363. ISSN 0021-9258 (doi:10.1074/jbc.M007929200)
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The tissue inhibitors of metalloproteinases (TIMPs) are a family of four secreted inhibitors of matrix metalloproteinases (MMPs). Recently, additional functions have been attributed to the TIMPs, including cell growth and inhibition of angiogenesis. In particular, we demonstrated that TIMP-3 overexpression using gene transfer induces apoptosis in a variety of cell types and can inhibit vascular neointima formation in vivo. However, little is know about the mechanisms underlying TIMP-3-mediated apoptosis. Here, using both purified recombinant proteins and novel adenoviral vectors we demonstrate that the prodeath domain of TIMP-3 is located within the N-terminal three loops of TIMP-3. Although both wild type and N-terminal TIMP-3 proteins promoted apoptosis, a T-2/T-3 chimera, in which the N-terminal three loops of TIMP-3 are replaced by those of TIMP-2, failed to induce cell death. Furthermore, a point mutation at residue 1 of TIMP-3 totally abolished MMP-inhibitory activity of TIMP-3 and also failed to promote apoptosis. This study demonstrates, using multiple apoptosis assays, that the prodeath function of TIMP-3 is located within the N-terminal three loops and the presence of functional metalloproteinase-inhibitory activity is associated with the induction of apoptosis.
|Glasgow Author(s) Enlighten ID:||Baker, Prof Andrew|
|Authors:||Bond, M., Murphy, G., Bennett, M., Amour, A., Knauper, V., Newby, A., and Baker, A.|
|College/School:||College of Medical Veterinary and Life Sciences|
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
|Journal Name:||Journal of Biological Chemistry|
|Journal Abbr.:||J Biol Chem.|
|Publisher:||American Society for Biochemistry and Molecular Biology, Inc.|