Role of Bcl-2 in Breast Cancer Progression
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-l, caspase, and bcl-2 family members play central roles in the commitment step. However, it is still unclear how upstream cell survival pathways, including cell adhesion signaling, regulate apoptosis. It is also unknown whether gene products regulating the apoptosis commitment step have any effect on the upstream survival pathways. Our study demonstrated that the anti-apoptotic gene product bcl-2 greatly induces expression of the tissue inhibitor of metalloprnteinase-l (TIMP-l), but not TlMP-2, in human breast epithelial cells. Surprisingly, we found that TIMP-l, like bcl-2, is a potent inhibitor of apoptosis induced by a variety of stimuli. TIMP-l constitutively activates focal adhesion kinase (FAK) independent of cell anchorage or cell-cell interactions and inhibits a classical apoptotic pathway mediated by caspases. Furthermore, we show that exogenous recombinant TIMP-l protects against apoptosis. Taken together, our study suggests that bcl-2 inhibition of apoptosis involves TIMP-l induction and TIMP-l binding on the cell surface induces a cell survival pathway that regulates apoptosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA391246
Entities
People
- Hyeong-reh Kim
Organizations
- Wayne State University