Abstract
Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double-negative stages. Using the OP9-DL1 system to deliver temporally controlled Notch receptor-dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation, and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active Akt, a downstream target of Notch signaling. These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / physiology
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Cell Differentiation / physiology
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Cell Growth Processes / physiology
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cyclin-Dependent Kinase 6 / biosynthesis
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Cyclin-Dependent Kinase 6 / deficiency
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Cyclin-Dependent Kinase 6 / genetics
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Cyclin-Dependent Kinase 6 / metabolism*
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Female
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Lymphoma / enzymology
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Lymphoma / genetics
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Lymphoma / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Oncogene Protein v-akt
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Receptors, Notch
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T-Lymphocytes / cytology
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T-Lymphocytes / enzymology*
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T-Lymphocytes / pathology
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Thymus Gland / cytology
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Thymus Gland / enzymology*
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Thymus Gland / pathology
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Thymus Neoplasms / enzymology*
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Thymus Neoplasms / genetics
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Thymus Neoplasms / pathology
Substances
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Receptors, Notch
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Oncogene Protein v-akt
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Cdk6 protein, mouse
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Cyclin-Dependent Kinase 6