CDK INHIBITORS P18(INK4C) AND P27(KIP1) MEDIATE 2 SEPARATE PATHWAYS TO COLLABORATIVELY SUPPRESS PITUITARY TUMORIGENESIS

INK4 and CIP/KIP are two distinct families of cyclin-dependent kinase (CDK) inhibitors implicated in mediating a wide range of cell growth c ontrol signals. We have created p18(INK4c)-deficient mice. These mice develop gigantism and widespread organomegaly. The pituitary gland, sp leen, and thymus are disproportionately enlarged and hyperplastic. T a nd B lymphocytes develop normally in p18-deficient mice, but both exhi bit increased cellularity and a higher proliferative rate upon mitogen ic stimulation. Loss of p18, like that of p27, but not other CDK inhib itor genes, leads to a gradual progression from intermediate lobe pitu itary hyperplasia in young mice to an adenoma by 10 months of age with a nearly complete penetrance. Mice lacking both pig and p27, like mic e chimeric for Rb deficiency, invariably died from pituitary adenomas by 3 months. Hence, pig and p27 mediate two separate pathways to colla boratively suppress pituitary tumorigenesis, likely by controlling the function of Rb.