期刊
CANCER CELL
卷 22, 期 4, 页码 452-465出版社
CELL PRESS
DOI: 10.1016/j.ccr.2012.09.016
关键词
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资金
- NIH/NCI [P30 CA016087-30, 5 P30CA16087-31]
- NYU Cancer Institute Center [5P30CA16087-31]
- National Institutes of Health [RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655, RO1GM088847]
- William Lawrence and Blanche Hughes Foundation
- Leukemia & Lymphoma Society
- V Foundation for Cancer Research
- Feinberg Lymphoma Grant
- Institute National du Cancer (INCa)
- NYU Molecular and Cellular Biology Training Program
- NYSTEM institutional NYU Stem Cell Training Grant [C026880]
D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.
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