BES2003 Poster Presentations Growth and Development (16 abstracts)
A potential role for human securin/PTTG in the developing human fetal brain
K Boelaert 1 , CJ McCabe 1 , LA Tannahill 1 , JN Bulmer 2 , SY Chan 3 , NJ Gittoes 1 , MC Sheppard 1 , MD Kilby 3 & JA Franklyn 1
1Division of Medical Sciences, University of Birmingham, Birmingham, UK; 2School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, UK; 3Division of Reproduction and Child Health, University of Birmingham, Birmingham, UK.
Human securin, known also as pituitary tumor transforming gene (PTTG), has established oncogenic and cell regulatory functions. PTTG transforms cells in vitro, inhibits sister chromatid separation and regulates secretion of fibroblast growth factor-2 (FGF-2). FGF-2 is a key regulator of CNS development and PTTG/securin expression has previously been reported in murine fetal brain. We examined mRNA and protein expression of PTTG and FGF-2 in 35 first trimester (7-12 weeks) and 26 second trimester (13-20 weeks) human fetal cerebral cortex samples and compared findings with expression in 12 normal adult cerebral cortex samples. Subsequently, we assessed the in vitro effects of PTTG on FGF-2 expression and cell proliferation in fetal neuronal N-Tera-2 (NT2) cells. We demonstrated significantly lower expression of PTTG mRNA and protein in the fetal cerebral cortex compared to adult cortex (P=0.019) and immunohistochemistry revealed more intense PTTG staining in adult than fetal neurons. Proliferating cell nuclear antigen (PCNA) expression demonstrated that high PTTG levels in adult brain were associated with absent cell proliferation. We detected no significant differences in FGF-2 mRNA between fetal and adult life, but FGF-2 protein was, like PTTG, lower in fetal brain. Transient transfection of wild type (WT) PTTG into NT2 cells resulted in a 1.8-fold induction of FGF-2 mRNA (n=6, P<0.01), which was abrogated by a C-terminal mutation of PTTG. In 3H-thymidine incorporation assays, low transient expression of PTTG (0.05 micrograms per well) resulted in a significant proliferative effect (150 % compared with vector only, P=0.05, n=12) whereas higher doses (1.0 microgram per well) inhibited cell turnover (66% reduction, P=0.006, n=12). Furthermore, the pro-proliferative effect of PTTG on NT2 cells was abrogated by the C-terminal mutation. Based on securin's role as a mitotic regulator and its differential expression in adult and fetal brain, we propose a potential role for human PTTG/securin in modulating cell proliferation and FGF-2 expression during human neurogenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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