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Submitted on December 8, 2003
Accepted on May 25, 2004
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, 02115 Boston, MA, USA; Osteoporosis and Bone Metabolic Unit, Department of Clinical Biochemistry and Endocrinology, Copenhagen University Hospital Hvidovre, DK-2650, Denmark; Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115.; 
enetics and Aging Research Unit, Department of Psychiatry-Neuroscience, Massachusetts General Hospital, Charlestown, MA 02129
* To whom correspondence should be addressed. E-mail: tfelt{at}dadlnet.dk.
Human securin, pituitary tumor transforming gene (PTTG), is a proto-oncogene. Here we report expressions of PTTG and its interacting protein, PTTG-binding factor (PBF) in human astrocytic cells. PTTG expression was higher in malignant cells than in primary astrocytes whereas, PBF was not. Using a xenotransplantable, glioma cell line (U87), we observed that ‘knocking down’ PTTG mRNA by RNA silencing (siRNA), inhibited serum-induced proliferation by 
50%. Furthermore, in U87 cells PTTG expression was upregulated by pro-malignant ligands EGF and TGF
, both at the protein and mRNA levels. PTTG induction by EGF receptor (EGFR) ligands could be blocked by the specific EGFR inhibitor, AG1478. HGF also induced PTTG, but to a lesser extent than EGF. Although, EGF stimulates HGF secretion in U87 cells, the effect of EGF on PTTG mRNA expression is independent of HGF as neutralizing antibody against HGF failed to abolish EGF-induced up-regulation of PTTG mRNA. PTTG mRNA was unchanged by incubating U87 cells with the pro-malignant growth factor TGF
, apoptosis inducing, TNF and ligands for nuclear receptors, such as retinoic acid- and retinoid X receptors, and peroxisome proliferator-activated receptor 
, known for their growth-inhibitory and apoptosis-inducing effects on gliomas. In addition, 17--estradiol and Ca2+, known to activate PTTG expression, did not change PTTG mRNA levels in U87 cells. In summary, we show higher PTTG expression in astrocytoma than normal astrocytes and secondly PTTG is involved in glioma cell growth. Finally regulation of its expression has glioma-specific features and is selectively regulated by promalignant cytokines including EGFR ligands and HGF.
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