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.