A Requirement for Cyclin-Dependent Kinase 6 in Thymocyte Development and Tumorigenesis

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 proliferati...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2009-02, Vol.69 (3), p.810-818
Main Authors: HU, Miaofen G, DESHPANDE, Amit, TSICHLIS, Philip N, GOUNARI, Fotini, HINDS, Philip W, ENOS, Miriam, DAQIN MAO, HINDS, Elisabeth A, HU, Guo-Fu, RUI CHANG, ZHUYAN GUO, DOSE, Marei, CHANGCHUIN MAO
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis - physiology
Biological and medical sciences
Cell Differentiation - physiology
Cell Growth Processes - physiology
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Cyclin-Dependent Kinase 6 - biosynthesis
Cyclin-Dependent Kinase 6 - deficiency
Cyclin-Dependent Kinase 6 - genetics
Cyclin-Dependent Kinase 6 - metabolism
Female
Lymphoma - enzymology
Lymphoma - genetics
Lymphoma - pathology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Oncogene Protein v-akt
Pharmacology. Drug treatments
Receptors, Notch
T-Lymphocytes - cytology
T-Lymphocytes - enzymology
T-Lymphocytes - pathology
Thymus Gland - cytology
Thymus Gland - enzymology
Thymus Gland - pathology
Thymus Neoplasms - enzymology
Thymus Neoplasms - genetics
Thymus Neoplasms - pathology
Tumors
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Description
Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-08-2473