한국응용약물학회:학술대회논문집 (Proceedings of the Korean Society of Applied Pharmacology)
- 한국응용약물학회 2002년도 창립10주년기념 및 국립독성연구원 의약품동등성평가부서 신설기념 국재학술대회:생물학적 동등성과 의약품 개발 전략을 위한 국제심포지움
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- Pages.89-96
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- 2002
TIMP-1 in the regulation of ECM and apoptosis
- Liu, Xu-Wen (Department of Pathology, Wayne State University School of Medicine, and Karmanos Cancer Institute) ;
- Jung, Ki-Kyung (Department of Pathology, Wayne State University School of Medicine, and Karmanos Cancer Institute) ;
- Kim, Hyeong-Reh-Choi (Department of Pathology, Wayne State University School of Medicine, and Karmanos Cancer Institute)
- 발행 : 2002.07.01
초록
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. We have demonstrated 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)/Pl 3-kinase and mitogen activated protein kinase (MAPK) are critical for TIMP- 1 -mediated cell survival. We also showed specific association of TIMP-1 with the cell surface. Consistently, a 150-H)a surface protein was identified in MCF10A cells that specifically binds TIMP-1. Taken together, we hypothesize that TIMP-I binding on the cell surface induces a cell survival pathway that regulates the common apoptosis commitment step. The results of these studies will 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 .
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