Accession Number:

ADA359618

Title:

Function of Cell Cycle Control Proteins in Breast Cancer

Descriptive Note:

Final rept. 1 Aug 94-31 Jul 98

Corporate Author:

HARVARD MEDICAL SCHOOL BOSTON MA

Personal Author(s):

Report Date:

1998-08-01

Pagination or Media Count:

32.0

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 pRbs 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.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE