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Expression of Pituitary Tumor Transforming Gene (PTTG) and Its Binding Protein in Human Astrocytes and Astrocytoma Cells: Function and Regulation of PTTG in U87 Astrocytoma Cells

Division of Endocrinology, Diabetes, and Hypertension (J.T.-H., S.Y., E.M.B., N.C.), Department of Medicine and Membrane Biology Program and Department of Neurosurgery (R.C.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; Osteoporosis and Bone Metabolic Unit (J.T.-H.), Department of Clinical Biochemistry and Endocrinology, Copenhagen University Hospital Hvidovre, DK-2650 Copenhagen, Denmark; and Genetics and Aging Research Unit (S.B.), Department of Psychiatry-Neuroscience, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Address all correspondence and requests for reprints to: Jacob Tfelt-Hansen, Laboratory of Molecular Cardiology, Department of Cardiology, University of Copenhagen, 20 Juliane Maries Vej, Section 9312, DK 2100 Copenhagen O, Denmark. E-mail: tfelt{at}dadlnet.dk.

Human securin, pituitary tumor transforming gene (PTTG), is a protooncogene. Here we report expressions of PTTG and its interacting protein, PTTG-binding factor in human astrocytic cells. PTTG expression was higher in malignant cells than in primary astrocytes, whereas PTTG-binding factor was not. Using a xenotransplantable, glioma cell line (U87), we observed that knocking down PTTG mRNA by RNA silencing inhibited serum-induced proliferation by approximately 50%. Furthermore, in U87 cells PTTG expression was up-regulated by promalignant ligands epithelial growth factor (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. Hepatocyte growth factor (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 promalignant growth factor TGFß, 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, 17ß-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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