Function of Cell Cycle Control Proteins in Breast Cancer.
Annual rept. 1 Aug 95-31 Jul 96,
HARVARD MEDICAL SCHOOL BOSTON MA
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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 the function of this growth regulatory protein. Overexpression of cyclin D1 is such an event, since high levels of this protein may 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 D1 is dispensable for phosphorylation and transformation by cyclin D1, but apparently not in the closely related cyclin D2. Instead, loss of a cyclin D1 domain just C-terminal the pRb-interaction domain may inactivate the protein. Using our knowledge of cyclin D1 function from these mutants and others, we hope to eventually create animal models of D1-dependent tumorigenesis useful for identifying suppressors of these tumors. p2
- Medicine and Medical Research