Pituitary Tumor-Transforming Gene: Physiology and Implications for Tumorigenesis

Pituitary tumor-transforming gene-1 (PTTG1) is overexpressed in a variety of endocrine-related tumors, especially pituitary, thyroid, breast, ovarian, and uterine tumors, as well as nonendocrine-related cancers involving the central nervous, pulmonary, and gastrointestinal systems. Forced PTTG1 expression induces cell transformation in vitro and tumor formation in nude mice. In some tumors, high PTTG1 levels correlate with invasiveness, and PTTG1 has been identified as a key signature gene associated with tumor metastasis. Increasing evidence supports a multifunctional role of PTTG1 in cell physiology and tumorigenesis. Physiological PTTG1 properties include securin activity, DNA damage/repair regulation and involvement in organ development and metabolism. Tumorigenic mechanisms for PTTG1 action involve cell transformation and aneuploidy, apoptosis, and tumorigenic microenvironment feedback. This paper reviews recent advances in our understanding of PTTG1 structure and regulation and addresses known mechanisms of PTTG1 action. Recent knowledge gained from PTTG1-null mouse models and transgenic animals and their potential application to subcellular therapeutic targeting PTTG1 are discussed. (Endocrine Reviews 28: 165-186, 2007) I. Introduction II. PTTG1 Gene Structure and Regulation A. PTTG1 gene structure B. PTTG1 mRNA expression profile C. Regulation of gene expression III. PTTG Protein A. PTTG1 protein structure B. PTTG1 protein subcellular localization and complex formation C. PTTG1 protein posttranscriptional modification IV. PTTG Family Members A. Cloning and characterization of PTTG2 and -3 B. PTTG family member expression profile V. PTTG1: Physiological Functions A. Securin function/replication B. DNA damage/repair C. Interaction partners and transactivation activity VI. PTTG1: