D-type cyclins (cyclin D1, D2 and D3) are the components of the core cell cycle machinery. The three D cyclins are expressed in an overlapping, redundant fashion in all proliferating cell types. D-cyclins are believed to serve as """"""""links"""""""" between the cell environment and the cell cycle machinery. Consistent with growth promoting functions for D-cyclins, chromosomal abnormalities of the cyclin D genes and overexpression of cyclin D proteins were reported in several human cancers. It is widely assumed that at least one of the three D-type cyclins must be present to allow normal cell proliferation. However, our recent observations that embryos lacking all three D-cyclins develop normally until mid-late gestation and die due to highly circumscribed abnormalities, indicate that this notion needs to be re-evaluated. Cyclin D1-/-D2-/-D3-/- embryos and cells offer us a unique tool to conclusively address the function for D-cyclins in controlling cell proliferation at the cellular and molecular levels. We hypothesize that the D-cyclins are dispensable for continuous cell cycling, but are critically required for cell cycle re-entry. In studies described in the first Aim, we will study the molecular function for D-cyclins in cell cycle progression using mutant embryos and in vitro grown D1-/-D2-/-D3-/- cells. We will also rigorously test the putative function of D-cyclins as regulators of transcription.
In Aim 2, we will address the requirement for D-cyclins in oncogenic cell proliferation using D1- /-D2-/-D3-/- cells. We will test our hypothesis that D-cyclins are critically required for malignant transformation by the activated Ras (and possibly, Myc). Lastly, in the Aim 3, we will test the requirement for D-cyclins in terminally differentiated cells using two approaches: (1) by creating chimeric mice composed of wild-type and DI-/-D2-/-D3-/- cells, and (2) by generating a conditional cyclin D knockout strain that will allow ubiquitous, sudden shut down of D-cyclins. Using this system we will study the consequences of cyclin D shutdown in terminally differentiated neurons, hepatocytes and muscle cells.
The Specific Aims are: 1. To determine the molecular function of D-cyclins using triple-knockout embryos and in vitro cultured triple knockout cells; 2. To determine the requirement for D cyclins in oncogenic transformation; 3. To study the function of D-cyclins in terminally differentiated cells of adult animals.
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