F14, R12, C43,

Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.

The pituitary tumor transforming gene, PTTG, is abundantly expressed in several neoplasms. We recently showed that PTTG overexpression is associated with apoptosis and therefore have now studied the role of p53 in this process. In MCF-7 breast cancer cells that express wild type p53, PTTG overexpression caused apoptosis. p53 was translocated to the nuclei in cells expressing PTTG. Overexpression of p53, along with PTTG, augmented apoptosis, whereas expression of the human papillomavirus E6 protein inhibited PTTG-induced apoptosis. In MG-63 osteosarcoma cells that are deficient in p53, PTTG caused cell cycle arrest and subsequent apoptosis that was inhibited by caspase inhibitors. A proteasome inhibitor augmented PTTG expression in stable PTTG transfectants, suggesting that down-regulated PTTG expression is required for cell survival. Finally, MG-63 cells expressing PTTG showed signs of aneuploidy including the presence of micronuclei and multiple nuclei. These results indicate that PTTG overexpression causes p53-dependent and p53-independent apoptosis. In the absence of p53, PTTG causes aneuploidy. These results may provide a mechanism for PTTG-induced tumorigenesis whereby PTTG mediates aneuploidy and subsequent cell transformation.

The mammalian securin, pituitary tumor transforming gene (PTTG), regulates sister chromatid separation during mitosis. Mice or cell lines deficient in PTTG expression, however, are surprisingly viable. Here we show that PTTG disruption in mice (PTTG؊͞؊) severely impairs glucose homeostasis leading to diabetes during late adulthood, especially in males associated with nonautoimmune insulinopenia and reversed alpha͞beta cell ratio. Islet beta cell mass in PTTG؊͞؊ mice was already diminished before development of frank diabetes and only increased minimally during growth. BrdUrd incorporation of islet cells in PTTG-null mice was Ϸ65% lower (P < 0.005) than in the WT pancreas, whereas apoptosis rates were similar. PTTG؊͞؊ beta cells had pleiotropic nuclei, suggesting defects in cell division. The results indicated that securin is indispensable for normal pancreatic beta cell proliferation. P ituitary tumor transforming gene (PTTG) was initially isolated from rat pituitary tumor cells and is functionally homologous to yeast securin (1, 2). Securin proteins together with separin and cohesin regulate sister chromatid separation during M phase of the cell cycle (2, 3). Securin accumulation and binding to separin during interphase and early mitosis prevents premature separin activation. During the normal cell cycle, the anaphase promoting complex eventually degrades securin, thus activating separin to facilitate equal chromosome segregation. In this sense, securin functions as an inhibitor of chromatid separation during anaphase (2, 3). Because securin is a highly conserved protein, and appears to be critical for cell division, it is surprising that PTTG loss seems not to be detrimental for mammalian cell survival; inactivation of human securin in a karyotypically stable colorectal cancer cell line resulted in a higher chromosome loss rate, whereas the cells remained viable (4). Securin PTTGϪ͞Ϫ mice generated in our laboratory are viable and fertile despite PTTGϪ͞Ϫ mouse embryo fibroblasts (MEFs) showing abnormal chromosome structure and aneuploidy in some cells (5).In this report, we show that securin is indispensable for pancreatic beta cell proliferation. Islet beta cell mass is smaller and grows at a much lower rate in PTTGϪ͞Ϫmice, especially males, in which diabetes develops in late adulthood. In addition, Ϸ3% of beta cells in PTTGϪ͞Ϫ mice are macronuclear, suggesting defects in cell division. The results demonstrate that securin plays a critical role in maintaining pancreatic beta cell division. Materials and MethodsAnimals. Securin PTTGϪ͞Ϫ mice have been described (5) and are kept in a hybrid background derived from C57͞BL6 and 129SvJ mouse strains. Animals were housed in a 12-h dark͞light cycle and fed standard chow ad libitum. Mice aged 2-13 mo were used for experiments. Food intake and urine production were measured in metabolic cages.Blood Sample Assays. Fasting blood glucose was measured using a DEX glucometer (Bayer). Serum concentrations of insulin and C-peptide were measured using RIA kits (Linco Research I...

Tumorigenic pituitary tumor transforming gene (PTTG) is a mammalian homolog of Xenopus securin that inhibits chromatid separation, is overexpressed in many human tumor types, and mediates transcriptional activation. Loss of yeast securin Pds1p or Drosophila securin pimples is lethal. Here we show that mice lacking PTTG (PTTG -/-) are, surprisingly, viable and fertile; but they have testicular and splenic hypoplasia, thymic hyperplasia, and thrombocytopenia. PTTG -/- mouse embryo fibroblasts exhibited aberrant cell cycle progression with prolonged G2-M phase and binucleated and multinucleated nuclei with increased aneuploidy. PTTG -/- mouse embryo fibroblast metaphases contained quadriradial, triradial, and chromosome breaks, as well as premature centromere division. The results show that PTTG functions to maintain chromosome stability, cell cycle progression, and appropriate cell division. Moreover, mammalian sister chromatid separation, an important transition in the cell cycle, is likely regulated by mechanisms in addition to securin.