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

2008 2008

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Abstract (summary)

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.

Indexing (details)

Molecular biology;
0307: Molecular biology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; Cell cycle; G1-S progression; Immunology; Notch signaling; T cell biology; T cells
The role of Notch in regulation of G1 -S progression of cell cycle in T cells
Joshi, Ila
Number of pages
Publication year
Degree date
School code
DAI-B 69/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Osborne, Barbara A.
Committee member
Goldsby, Richard A.; Smith Schneider, Sallie; Telfer, Janice C.
University of Massachusetts Amherst
Molecular & Cellular Biology
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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