Regulation of the Calcium-Calmodulin-Dependent Kinase Cascade in Human Breast Cancer Cells.
Abstract
The regulation of the CaM KI signaling pathway will be studied in human breast cancer cell lines. We hypothesize that CaM KI phosphorylation of the transcription factor, CREB is a key regulatory step in cell cycle regulation and/or prevention of apoptosis. Since tamoxifen (TAM) causes cell cycle arrest and apoptosis in breast cancer cells, we thought that part of TAM's effects may be mediated by inhibition of the CaM kinase cascade. Regardless if this is the case, CaM inhibitors cause cell cycle arrest and apoptosis in many tumor cells. Hence, CaM and its targets are potential sites of therapeutic intervention. We have found that TAM does not inhibit CaM activation of CaM KI as originally proposed. We have found, however, that Ca2+ not only modulates the phosphorylation of S133 of CREB, but also CREB binding protein (CBP) transactivation. In characterizing the mechanism of CaM KI activation by CaM KI, we found that the substrate specificity of CaM KI changes upon T177 phosphorylation by CaM KI. These data will be very relevant to how CaM KI can function in breast cancer cells, particularity if different substrates require alternate modes of enzyme activation. As cells reenter the cell cycle from growth arrest, CaM KI expression dramatically peaks. It will be interesting to see at which stages during the cell cycle CaM KI is functionally important and whether these stages are compromised in our human breast cancer cell lines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA353791
Entities
People
- Sara S. Hook
Organizations
- Duke University