Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53

Praveen Kumar, Ulrike Naumann, Ludwig Aigner, Joerg Wischhusen, Christoph P. Beier, Dagmar Beier

Research output: Contribution to journalArticle

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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 p53mut/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 p53wt/wt but not in p53mut/mut NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53wt/wt but not of p53mut/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.

Original languageEnglish
Pages (from-to)3436-3445
Number of pages10
JournalAmerican Journal of Cancer Research
Volume5
Issue number11
Publication statusPublished - 01-01-2015
Externally publishedYes

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Neural Stem Cells
Transforming Growth Factor beta
Stem Cells
Growth
Lateral Ventricles
Glioma
Transforming Growth Factor beta Receptors
Mitogens
Hyperplasia
Neoplasms
Phosphorylation
Pharmacology

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kumar, Praveen ; Naumann, Ulrike ; Aigner, Ludwig ; Wischhusen, Joerg ; Beier, Christoph P. ; Beier, Dagmar. / Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53. In: American Journal of Cancer Research. 2015 ; Vol. 5, No. 11. pp. 3436-3445.
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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 p53mut/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 p53wt/wt but not in p53mut/mut NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53wt/wt but not of p53mut/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.",
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Kumar, P, Naumann, U, Aigner, L, Wischhusen, J, Beier, CP & Beier, D 2015, 'Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53', American Journal of Cancer Research, vol. 5, no. 11, pp. 3436-3445.

Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53. / Kumar, Praveen; Naumann, Ulrike; Aigner, Ludwig; Wischhusen, Joerg; Beier, Christoph P.; Beier, Dagmar.

In: American Journal of Cancer Research, Vol. 5, No. 11, 01.01.2015, p. 3436-3445.

Research output: Contribution to journalArticle

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AU - Naumann, Ulrike

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AU - Beier, Dagmar

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