Human pituitary tumors of a gonadotroph cell origin represent up to 30% of all diagnosed pituitary neoplasms. Clinically, these tumors cause considerable morbidity because of mass effect, resulting in cranial nerve compression syndromes, including visual loss and other neurologic deficits, and there are no established adjunctive medical therapies to control tumor growth. A major finding regarding the pathogenesis of human pituitary tumors in our previous grant record period was that such tumors are monoclonal in origin, demonstrating that a somatic mutation is a requisite event in tumor formation. The next critical questions are what mechanisms underlie selective clonal proliferation in pituitary tumors, and what mechanisms underlie the pathogenesis of specific adenoma phenotypes. We have now isolated a pituitary-derived anti-proliferative gene PDAP, a novel gene which inhibits cell proliferation. This gene is expressed in normal human pituitary tissue but not in most human pituitary tumors as well as other human cancer cells. We propose to investigate the structure, function, and regulation of this novel gene as well as the mechanisms by which it suppresses tumor cell growth. We will characterize the gene structure of PDAP and investigate its promoter activities in normal and tumor cells. We will investigate the relationship between PDAP and cell growth. In addition, we will determine whether PDAP is expressed and functions in a cell type-specific manner in human pituitary. The discovery of a novel gene with antiproliferative effects is an exciting new finding. Investigation of the mechanism for the loss of PDAP expression in human tumors will provide important information regarding the pathogenesis of human pituitary adenomas, and, potentially, other human tumors.
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