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    Research Grants Awarded

    A Genetic Screen for Cyclin D Redundant Pathways in the Cell Cycle

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    D-type cyclins (cyclin D1, D2, and D3) are believed to represent critical links between cell environment and the core cell cycle machinery. Consistent with their growth-promoting roles, overexpression of the D-type cyclins is seen in many human malignancies. The best-documented of these is the causative role for cyclin D1-overexpression in the majority of mammary carcinomas. Until very recently it was believed that the D-cyclins are essential for cell cycle progression. This dogma was recently challenged by the Sicinski laboratory. Specifically, the laboratory demonstrated that cyclin D-null mice develop till mid-gestation, and that the vast majority of cell types can proliferate normally in the absence of D-cyclins. These results reveal the presence of additional, previously unanticipated cyclin D-independent pathways that control cell proliferation. The availability of cyclin D-null cells in Dr. Sicinski’s laboratory offers me a unique tool to decipher the molecular basis of these cyclin D-independent pathways. In the proposed work, I will use libraries of short hairpin (sh)RNAs, to search for targets that are required for the proliferation of cyclin D-null but not wild-type cells. A similar approach will be used to search for targets that are required for proliferation of cells lacking E-type cyclins (which are also available in Dr. Sicinski laboratory). I hypothesize that these alternative, cyclin-independent pathways play role in these breast cancers that do not overexpress cyclins (25% of cases). I will study this possibility in Aim 3. Hence, my work may uncover a novel mechanism for human breast cancer.

    Lay Abstract:
    D-type cyclins (cyclin D1, D2, and D3) represent a group of proteins that control cell division. Abnormally high levels of D-cyclins are seen in many human cancers. The best-documented of these is the causative role for high levels of cyclin D1 in the majority of mammary carcinomas. Until very recently it was believed that the D-cyclins are essential for cell division. This dogma was recently challenged by the Sicinski laboratory. Specifically, the laboratory demonstrated that the vast majority of cell types can divide normally in the absence of D-cyclins. These results reveal the presence of additional, previously unanticipated cyclin D-independent mechanisms that control cell division. The availability of cells lacking D-cyclins in Dr. Sicinski’s laboratory offers me a unique tool to decipher the molecular basis of these cyclin D-independent mechanisms. In the proposed work, I will use the very novel, emerging technology called ‘libraries of short hairpin (sh)RNAs’ to elucidate the molecular mechanisms of cyclin D-independent cell division. I hypothesize that these alternative, cyclin-independent pathways play role in these breast cancers that do not over-express cyclins. I will study this possibility in Aim 3. Hence, my work may uncover a novel mechanism for human breast cancer.