TIMP-1 Regulation of ECM and Apoptosis
Abstract
The importance of apoptosis in normal development and pathogenesis has been well recognized, and explosive progress towards dissecting its commitment step has been made during the past decade. Mitochondria, Apaf-1, caspase, and bcl-2 family members play central roles in the commitment step. However, it is still unclear how upstream cell survival pathways regulate apoptosis. It is also unknown whether the bcl-2 family members have any effect on the upstream survival pathways. Our studies demonstrate that the anti-apoptotic gene product bcl-2 greatly induces expression of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in human breast epithelial cells. Surprisingly, we found that TIMP-1, like bcl-2, is a potent inhibitor of apoptosis induced by a variety of stimuli. Functional studies indicate that TIMP-1 inhibits a classical apoptotic pathway mediated by caspases, and that focal adhesion kinase (FAK)/PI 3-kinase and mitogen activated protein kinase (MAPK) are critical for TIMP-1-mediated cell survival. We show specific association of TIMP-1 with the cell surface. Consistently, a 150-kDa surface protein was identified in MCF10A cells that specifically binds TIMP-1. Taken together, we hypothesize that TIMP-1 binding on the cell surface induces a cell survival pathway that regulates the common apoptosis commitment step. Our studies address a new paradigm in the regulation of apoptosis by an extracellular molecule TIMP-1, and also greatly enhance our understanding of TIMP-1's pleiotropic activity in many physiological and pathological processes. This information may also be useful in designing more rational therapeutic interventions aimed at modulating the anti-apoptotic activity of TIMP-1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2002
- Accession Number
- ADA405238
Entities
People
- Hyeong-reh C. Kim
Organizations
- Wayne State University