title: Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53.
abstract: Gliomas have been classified according to their histological properties. However, their respective cells of origin are still unknown. Neural progenitor cells (NPC) from the subventricular zone (SVZ) can initiate tumors in murine models of glioma and are likely cells of origin in the human disease. In both, p53 signaling is often functionally impaired which may contribute to tumor formation. Also, TGF-beta, which under physiological conditions exerts a strong control on the proliferation of NPCs in the SVZ, is a potent mitogen on glioma cells. Here, we approach on the crosstalk between p53 and TGF-beta by loss of function experiments using NPCs derived from p53 mutant mice, as well as pharmacological inhibition of TGF-beta signaling using TGF-beta receptor inhibitors. NPC derived from p53 mutant mice showed increased clonogenicity and more rapid proliferation than their wildtype counterparts. Further, NPC derived from p53(mut/mut) mice were insensitive to TGF-beta induced growth arrest. Still, the canonical TGF-beta signaling pathway remained functional in the absence of p53 signaling and expression of key proteins as well as phosphorylation and nuclear translocation of SMAD2 were unaltered. TGF-beta-induced p21 expression could, in contrast, only be detected in p53(wt/wt) but not in p53(mut/mut) NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53(wt/wt) but not of p53(mut/mut) NPC. In conclusion, our data suggest that the TGF-beta induced growth arrest in NPC depends on functional p53. Mutational inactivation of p53 hence contributes to increased proliferation of NPC and likely to the formation of hyperplasia of the SVZ observed in p53 deficient mice in vivo.
authors.affiliation: Department of Neurology, RWTH AachenPauwelsstrasse 30, Aachen 52074, Germany; Present Address: Department of Biotechnology, Manipal Institute of Technology, Manipal UniversityManipal - 576104, Karnataka, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tuebingen Otfried-Müller-Str. 27, Tuebingen 72076, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Naumann
authors.affiliation: Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Austria.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
authors.affiliation: Interdisciplinary Center for Clinical Research, University of Würzburg, Medical School, Clinics for Gynecology and Obstetrics Josef-Schneider-Str. 4, Würzburg 97080, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wischhusen
authors.affiliation: Department of Neurology, RWTH AachenPauwelsstrasse 30, Aachen 52074, Germany; Department of Neurology, University Hospital Odense and Clinical Institute, University of Southern DenmarkSdr. Boulevard 29, Odense 5000, Denmark.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Beier
authors.affiliation: Department of Neurology, RWTH AachenPauwelsstrasse 30, Aachen 52074, Germany; Department of Neurology, University Hospital Odense and Clinical Institute, University of Southern DenmarkSdr. Boulevard 29, Odense 5000, Denmark.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Beier
keywords: Neural stem cell; TGF-beta; glioblastoma stem cell; p53; premalignant lesion; subventricular zone