Brain Advance Access originally published online on June 8, 2009
Brain 2009 132(8):2277-2288; doi:10.1093/brain/awp153
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Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer Centre, Houston, TX 77030, USA 2 Department of Bioinformatics and Computational Biology, University of Texas, M. D. Anderson Cancer Centre, Houston, TX 77030, USA 3 Department of Cancer Genetics, University of Texas, M. D. Anderson Cancer Centre, Houston, TX 77030, USA
Correspondence to: Gilbert J. Cote, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA and Graduate Program in Human and Molecular Genetics, University of Texas at Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA E-mail: gcote{at}mdanderson.org
Polypyrimidine tract-binding protein 1 (PTBP1) is a multi-functional RNA-binding protein that is aberrantly overexpressed in glioma. PTBP1 and its brain-specific homologue polypyrimidine tract-binding protein 2 (PTBP2) regulate neural precursor cell differentiation. However, the overlapping and non-overlapping target transcripts involved in this process are still unclear. To determine why PTBP1 and not PTBP2 would promote glial cell-derived tumours, both PTBP1 and PTBP2 were knocked down in the human glioma cell lines U251 and LN229 to determine the role of these proteins in cell proliferation, migration, and adhesion. Surprisingly, removal of both PTBP1 and PTBP2 slowed cell proliferation, with the double knockdown having no additive effects. Decreased expression of both proteins individually and in combination inhibited cell migration and increased adhesion of cells to fibronectin and vitronectin. A global survey of differential exon expression was performed following PTBP1 knockdown in U251 cells using the Affymetrix Exon Array to identify PTBP1-specific splicing targets that enhance gliomagenesis. In the PTBP1 knockdown, previously determined targets were unaltered in their splicing patterns. A single gene, RTN4 (Nogo) had significantly enhanced inclusion of exon 3 when PTBP1 was removed. Overexpression of the splice isoform containing exon 3 decreased cell proliferation to a similar degree as the removal of PTBP1. These results provide the first evidence that RNA-binding proteins affect the invasive and rapid growth characteristics of glioma cell lines. Its actions on proliferation appear to be mediated, in part, through alternative splicing of RTN4.
Key Words: PTBP1; PTBP2; RTN4; glioma; RNA splicing
Abbreviations: PTBP1, polypyrimidine tract-binding protein 1; PTBP2, polypyrimidine tract-binding protein 2
Received December 13, 2008. Revised April 25, 2009. Accepted April 27, 2009.
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