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

Am J Cancer Res, 2015 · DOI: · Published: November 1, 2015

Simple Explanation

Glioblastoma is a deadly brain tumor, and its origin is debated. Neural progenitor cells (NPC) might be the source, with impaired p53 signaling playing a role. TGF-beta normally controls NPC proliferation but acts as a mitogen in glioma cells. This study explores the connection between p53 and TGF-beta using NPC from p53 mutant mice and TGF-beta inhibitors. The study found that NPC from p53 mutant mice proliferate faster and are resistant to TGF-beta-induced growth arrest, suggesting that functional p53 is needed for TGF-beta to control NPC growth.

Study Duration

Not specified

Participants

NPC derived from p53 mutant mice

Evidence Level

Not specified

Key Findings

1
NPC derived from p53 mutant mice exhibit increased clonogenicity and a more rapid proliferation rate compared to their wildtype counterparts.
2
NPC from p53mut/mut mice are insensitive to TGF-beta induced growth arrest, while the canonical TGF-beta signaling pathway remains functional.
3
TGF-beta-induced p21 expression is only detected in p53wt/wt NPC and not in p53mut/mut NPC, indicating p53's role in TGF-beta mediated growth inhibition.

Research Summary

This study investigates the crosstalk between p53 and TGF-beta signaling in neural progenitor cells (NPC) derived from p53 mutant mice, focusing on the impact on cell proliferation and growth arrest. The key finding is that mutational inactivation of p53 contributes to increased proliferation of NPC by impairing TGF-beta induced growth arrest, leading to a loss of TGF-beta mediated p21 induction. The research suggests that p53 dysfunction may predispose NPC towards the formation of glial tumors by disrupting TGF-beta dependent mechanisms controlling neurogenesis.

Practical Implications

Targeted Therapies

Understanding the interplay between p53 and TGF-beta could lead to more targeted therapies for gliomas, especially those with p53 mutations.

Early Detection

Identifying p53 dysfunction in NPC could help in early detection of premalignant lesions in the brain.

Aging Brain Research

The dependence of TGF-beta's effect on p53 could provide insights into age-related changes in neurogenesis and potential interventions.

Study Limitations

1
The in vivo proof-of-concept of this hypothesis in a relevant tumor model would have been beyond the scope of this study.
2
P53 also limits the proliferation of NPC by TGF-beta independent signaling pathways not explored in this study.
3
Possible effects of p53 inactivation on neurogenesis were not investigated in our study.

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