CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis
- David S. Franklin1,
- Virginia L. Godfrey2,
- Hayyoung Lee3,
- Grigoriy I. Kovalev1,4,
- Robert Schoonhoven5,
- Selina Chen-Kiang3,
- Lishan Su1,4, and
- Yue Xiong1,6,7,8
- 1Lineberger Comprehensive Cancer Center, 2Department of Pathology and Laboratory Medicine, 4Department of Microbiology and Immunology, 5Department of Environmental Sciences and Engineering, 6Department of Biochemistry and Biophysics, and 7Program in Molecular Biology and Biotechnology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA; 3Department of Pathology, Cornell University Medical College, New York, New York 10021 USA
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 p18INK4c-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.
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Footnotes
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↵8 Corresponding author.
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E-MAIL yxiong{at}email.unc.edu; FAX (919) 966-8799.
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- Received June 10, 1998.
- Accepted July 31, 1998.
- Cold Spring Harbor Laboratory Press
