Pituitary Tumor Transforming Gene: An Update

Abstract

Herein we summarize the recent rapid advances in understanding the pituitary tumor transforming gene (PTTG) oncogene. Clinical studies reveal that PTTG-binding factor, fibroblast growth factor 2, and vascular endothelial growth factor are elevated in pituitary tumors, and mostly correlate with PTTG levels, also confirming the PTTG role in angiogenesis. PTTG overexpression disrupts mitosis and causes aneuploidy in single live cells and PTTG modulates p53 activity and p53 also mediates DNA damage-induced inhibition of PTTG transcription. Physiological functions of PTTG are revealed by PTTG-null mice who exhibit a variety of cell growth abnormalities including diabetes mellitus secondary to defective beta-cell proliferation. PTTG is therefore an oncogene for pituitary tumors and other neoplasia, and also involved in critical metabolic functions. Further studies are required to address mechanisms for these oncogenic and physiological functions, and more importantly, to understand conditions which determine the switch of PTTG from functioning physiologically to behaving as an oncogene.

Expression and possible role of hPTTG1/securin in cutaneous malignant melanoma

“…8,15,16 In normal cells, the securin protein is expressed in a cell-cycle-dependent manner and regulates sister chromatid separation to opposite poles of the cell during anaphase. 4 Following cytoplasmic to nuclear translocation, it peaks in the G2/M phase and subsequently is ubiquitinated and degraded in the proteasome. The process of sister chromatid segregation is tightly regulated and ensures that a complete set of chromosomes is transmitted from one generation to another.…”

“…At the metaphase-toanaphase transition, securin is degraded by a multisubunit protein ligase, the anaphase-promoting complex (APC) or cyclosome (APC/C) that is bound to accessory factors Cdc20 and Cdh1. 4 Overexpression of securin may be caused by several mechanisms. First, genomic aberrations in hPTTG1 (promoter mutations, amplification) have as yet not been detected, or do not play a major role in the enhanced transcription or insufficient degradation of securin.…”

“…11 Forced overexpression of hPTTG1 in human embryonic kidney cells or NIH3T3 fibroblasts leads to an increased expression of angiogenic factors such as bFGF, VEGF and interleukin 8. 4,11,38 These factors may act as effectors for securin-driven angiogenesis since they contain a proline-rich SH3 domain that binds to the C-terminal double PXXP motif of securin, a putative SH3-interacting domain. 39 Ishikawa et al 11 showed that hPTTG1 induces an angiogenic phenotype in both in vitro and in vivo angiogenesis models.…”

“…2,3 hPTTG1 is a proto-oncogene encoding for securin, a protein involved in several metabolic reactions, cellcycle progression, appropriate cell division and chromosome stability; upon overexpression, securin is involved in malignant transformation and tumorigenesis. 4 In normal tissues, securin expression is limited, in contrast to many human tumours, including pituitary adenomas, 5 lung and breast cancer, [5][6][7] colorectal cancer, 8 oesophageal cancer 9 and some lymphoid neoplasms. 10 The oncogenic mechanisms of hPTTG1 are still barely known, but there is accumulating evidence that the oncoprotein activity of securin is exerted at different levels, that is, by induction of angiogenesis through basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), 11 by prevention of separation of sister chromatids resulting in aneuploidy, 12 by activation of c-myc 13 and/or by specific interaction with p53, thereby blocking its transcriptional activity and inhibiting the ability of p53 to induce cell death.…”

Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo

“…10,11 Clinical studies show that fibroblast growth factor 2 and vascular endothelial growth factor are elevated in pituitary tumors and mostly correlate with PTTG levels, suggesting the role of PTTG in angiogenesis. 12 PTTG1 is one of 17 genes representing metastasis in solid tumors. 13 Thus, PTTG1 is considered an oncogene for pituitary tumors and other neoplasia.…”