D-type cyclins (cyclin D1, D2, and D3) are the ultimate recipients of all mitogenic and oncogenic signals. While aberrant expression of D-cyclins is seen in many human malignancies, virtually all human cancers contain lesions in pathways impacting on D-cyclins. In order to understand specific roles played by cyclins D1 and D2, the applicant has previously generated knockout mouse strains lacking these proteins. He has found that these cyclin D1-/- and cyclin D2-/- mice display very circumscribed developmental abnormalities, revealing that each of the D-cyclins is required for proliferation only in a very limited, highly-specific set of tissues. He has now extended his analyses to cyclin D3, by generating cyclin D3-deficient mice. Based on the expression pattern of this cyclin, he predicts that cyclin D3 plays a specific role in driving development and proliferation of some lymphoid lineages. Consequently, he expects that mice lacking cyclin D3 will display proliferative deficiencies within the lymphoid compartment. He will test this possibility by analyzing lymphoid development of cyclin D3-deficient animals. He further hypothesizes that cyclin D2 and D3 drive the proliferation of all lymphoid lineages in a partially redundant fashion. He predicts that while deletion of single cyclin genes causes very narrow abnormalities, the combined ablation of two cyclins, D2 and D3, will lead to a dramatic impairment of lymphoid development. He will test this notion by generating cyclin D2-/-D3-/- mice and by analyzing their lymphoid development. Finally, he will study the roles for cyclins D2 and D3 in malignant proliferation of lymphoid cells. In particular he will test the following hypotheses: (i) cyclin D2 is required for the development of B cell leukemias in mice; (ii) cyclin D3 is overexpressed in a subset of human lymphoid malignancies.
The specific aims are as follows: (1) To determine the role played by cyclin D3 in lymphoid development. (2) To determine the consequence of combined ablation of cyclins D2 and D3 for lymphoid development. (3) To determine the role for cyclins D2 and D3 in lymphoid malignancies.
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