Pituitary Adenomas: Role of Cyclin-Dependent Kinase Inhibitors

Human pituitary adenomas are common tumors. In spite of extensive investigations, the molecular basis of human pituitary tumorigenesis remains elusive. The cell cycle is driven by cyclins-cyclin-dependent kinases (CDKs) complexes. Because CDK inhibitors (CKIs) serve as negative regulators of cell cycle, dysregulation in CKIs is recognized as critical factors in tumorigenesis. In recent years, extensive studies have demonstrated that somatic mutations, underexpression, and DNA methylation of the CKIs genes were frequently observed in various types of human cancers. Although the role of CKIs in human pituitary tumors has been elucidated to a limited extent, studies on knockout mice suggested that some CKIs are involved in tumorigenesis of murine pituitary gland. For example, knockout mice of p18Ink4c and p27Kip1 develop both pituitary intermediate- and anterior-lobe tumors and intermediate-lobe tumors, respectively. Each of the INK4 and CIP/KIP family members shows unique pattern of gene expression, mutations and promoter methylation in human pituitary adenomas. Until now, changes of mRNA or protein levels of p16INK4A, p18INK4C, and p27KIP1 in pituitary adenomas have been reported. Non-functioning pituitary adenomas show reduced expression of p16INK4A by epigenetic changes. In pituitary adenomas, mRNA and protein levels of p18INK4C were reduced by unidentified mechanisms and ­protein levels of p27KIP1 are reduced by protein modification. These changes of expression ­levels may contribute to pituitary tumorigenesis.