Function of Cell Cycle Control Proteins in Breast Cancer
Abstract
Loss of the retinoblastoma tumor suppressor protein (pRb) can contribute to breast tumor formation. However, many breast tumors retain expression of normal pRb, indicating that other genetic events may interfere with pRb's function. For example, overexpression of cyclin D1 can lead to constitutive inactivation of pRb through phosphorylation. We have demonstrated that cyclin D1 in oncogenic in cultured cells, and are using this assay to define regions and functions of cyclin D1 needed for transformation. Interestingly, a previously defined pRb-interaction domain in cyclin Dl is dispensable for phosphorylation and transformation, and a mutant of cyclin D1 incapable of kinase activation retains partial ability to inactivate pRb. These data suggest that cyclin D1 may have a unique method of circumventing pRb function that is independent of physical association with pRb and phosphorylation. We are creating animal models expressing cyclin D1 mutants that will allow a true in vivo determination of cyclin D1 functional domains in breast development and cancer. We have also produced and characterized a temperature sensitive pRb that is being used to identify gene targets of pRb. This mutant has revealed a cell-death effect resulting from pRb loss that may be due to the establishment of a pRb-directed, terminal cell cycle exit consistent with senescence.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 1998
- Accession Number
- ADA359618
Entities
People
- Phillip W. Hinds
Organizations
- Harvard Medical School