Structure, expression, and function of human pituitary tumor-transforming gene (PTTG)

Despite advances in characterizing the pathophysiology and genetics of pitu itary tumors, molecular mechanisms of their pathogenesis are poorly underst ood. Recently, we isolated a transforming gene [pituitary tumor-transformin g gene (PTTG)] from rat pituitary tumor cells. Here we describe the cloning of human PTTG, which is located on chromosome 5q33 and shares striking seq uence homology with its rat counterpart. Northern analysis revealed PTTG ex pression in normal adult testis, thymus, colon, small intestine, brain, lun g, and fetal liver, but most abundant levels of PTTG mRNA were observed in several carcinoma cell lines. Stable transfection of NIH 3T3 cells with hum an PTTG cDNA caused anchorage-independent transformation in vitro and induc ed in vivo tumor formation when transfectants were injected into athymic mi ce. Overexpression of PTTG in transfected NIH 3T3 cells also stimulated exp ression and secretion of basic fibroblast growth factor, a human pituitary tumor growth-regulating factor. A proline-rich region, which contains two P XXP motifs for the SH3 domain-binding site, was detected in the PTTG protei n sequence. When these proline residues were changed by site-directed mutag enesis, PTTG in vitro transforming and in vivo tumor-inducing activity, as well as stimulation of basic fibroblast growth factor, was abrogated. These results indicate that human PTTG, a navel oncogene, may function through S H3-mediated signal transduction pathways and activation of growth factor(s) .