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CDK inhibitors p18 INK4c and p27 Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis

1998; Cold Spring Harbor Laboratory Press; Volume: 12; Issue: 18 Linguagem: Inglês

10.1101/gad.12.18.2899

1549-5477

David S. Franklin, Virginia Godfrey, Hayyoung Lee, Kovalev Gi, Robert Schoonhoven, Selina Chen‐Kiang, Lishan Su, Yue Xiong,

Cancer Research and Treatments

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.