The inter-relationship between insulin and the Pituitary Tumor Transforming Gene (PTTG) in human tumorigenesis

Cancer is a complex disease that affects millions of people worldwide. Although various advances in cancer research have been achieved in the last decade, the cause of many tumors remains unknown. Recent studies have demonstrated that overexpression of the oncogenic Pituitary Tumor Transforming Gene (PTTG) stimulates tumor development and progression in various cells. It is a multifunctional proto-oncogene that is highly expressed in most of the tumors analyzed to date. PTTG mediates its tumorigenic functions through various pathways that regulate cell cycle progression, growth factor production, and oncogenic gene transcription. While it is known that PTTG gene expression is specifically activated in tumor cells, however, the factors that regulate the transcription of PTTG remain unknown.; Hyperinsulinemia is a condition characterized by elevated levels of insulin circulating in the blood. Contemporary reports indicate that patients who are hyperinsulinemic are predisposed to developing various tumors such as colorectal, endometrial, and breast carcinomas. A large and growing body of evidence suggests that the mitogenic effects of insulin may contribute to tumor development and progression. However, even though the two major signaling pathways induced by insulin, the Phosphatidylinositol 3-kinase (PI3K) and Mitigen-Activated Protein Kinase (MAPK) pathways have been characterized, however, the mechanisms by which insulin mediates its proliferative effects remain unclear. We hypothesize that the proto-oncogenic PTTG, which is phosphorylated by MAPK, may contribute to and/or serve as a downstream target for insulin's mitogenic function. This is supported by identification of an uncharacterized insulin responsive element (IRE) in the 5' flanking region of the PTTG gene.; To explore this hypothesis we treated breast cancer cell line MCF-7 cells with insulin and observed a time-dependent, dose-dependent and P13K/AKT signaling pathway-dependent activation of PTTG expression. To further confirm this novel activation of PTTG, actinomycin D and promoter activity experiments demonstrated that insulin stimulated new synthesis of PTTG. In our IRE experiments we were able to knockout insulin's stimulatory effect using site-directed mutagenesis and 5' deletions of the PTTG promoter. From this study we conclude that PTTG is regulated by insulin and that PTTG may serve as a downstream target for the mitogenic function of insulin.