Abstract
INK4 and CIP/KIP are two distinct families of cyclin-dependent kinase (CDK) inhibitors implicated in mediating a wide range of cell growth control signals. We have created p18(INK4c)-deficient mice. These mice develop gigantism and widespread organomegaly. The pituitary gland, spleen, and thymus are disproportionately enlarged and hyperplastic. T and B lymphocytes develop normally in p18-deficient mice, but both exhibit increased cellularity and a higher proliferative rate upon mitogenic stimulation. Loss of p18, like that of p27, but not other CDK inhibitor genes, leads to a gradual progression from intermediate lobe pituitary hyperplasia in young mice to an adenoma by 10 months of age with a nearly complete penetrance. Mice lacking both p18 and p27, like mice chimeric for Rb deficiency, invariably died from pituitary adenomas by 3 months. Hence, p18 and p27 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis, likely by controlling the function of Rb.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoma / etiology
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Adenoma / genetics
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Adenoma / prevention & control
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Animals
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Body Constitution / genetics
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Cycle Proteins*
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Cell Division / genetics
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Cell Division / physiology
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Cyclin-Dependent Kinase Inhibitor p18
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Enzyme Inhibitors / metabolism*
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Female
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Gene Targeting
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Lymphocyte Activation / genetics
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Lymphocyte Activation / physiology
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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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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / physiology*
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Pituitary Neoplasms / etiology
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Pituitary Neoplasms / genetics
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Pituitary Neoplasms / prevention & control*
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Splenomegaly / etiology
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Splenomegaly / genetics
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Tumor Suppressor Proteins*
Substances
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Carrier Proteins
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Cdkn1b protein, mouse
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Cdkn2c protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p18
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases