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The role of Notch in regulation of G1 -S progression of cell cycle in T cells

Ila Joshi, University of Massachusetts Amherst


Notch signaling is critical for the regulation of differentiation, proliferation and apoptosis in many cell types. Notch receptors and various Notch ligands have been shown to have a regulatory effect on cell cycle progression during the processes of development and differentiation. Cyclins are proteins that regulate cell cycle check-points, thereby controlling cell cycle progression. The D-cyclins, specifically, are required for overcoming the G1/S checkpoint. It has been shown previously (Ronchini et al) that NotchIC regulates the expression of Cyclin D1, one member of the Cyclin-D family. It has also been reported (Sicinska et al.) that Cyclin D3-/- mice display impaired thymocyte development and do not develop Notch1-induced leukemia. Based on these observations, we hypothesized that cyclin D3 may be a downstream target of Notch signaling in T cells. We observed that T cell receptor signaling increases Cyclin D3, cdk4 and cdk6 expression in peripheral T cells and inhibiting Notch activity reduces Cyclin D3, cdk4 and cdk6 expression in activated T cells. Using reporter assays, as well as chromatin immunoprecipitation, we show that the transactivation domain of Notch1 is critical for regulating the Cyclin D3 promoter. We demonstrate that cyclin D3-cdk4 and cdk6 is also responsible for cell cycle progression in Notch-dependent human T-ALL cell lines. We show that Cyclin D3 and cdk4/6 are important targets in constitutively active Notch signaling in leukemic T cells, as they can partially override the G1 arrest observed with GSI treatment. Together, our data indicate that Notch signaling controls peripheral and leukemic T cell proliferation. Furthermore, we have begun to outline a possible mechanism for the regulated expression of Cyclin D3 and cdk4/6 in leukemic T cells, and through our future experiments we hope to reveal the oncogenic potential of Cyclin D3 as a target of dysregulated Notch1 signaling.

Subject Area

Molecular biology|Immunology

Recommended Citation

Joshi, Ila, "The role of Notch in regulation of G1 -S progression of cell cycle in T cells" (2008). Doctoral Dissertations Available from Proquest. AAI3315502.