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Loss of p53 enhances NF-κB-dependent lamellipodia formation
Abstract:
Tumor suppressor p53 prevents tumorigenesis and tumor growth by suppressing the activation of several transcription factors, including nuclear factor-κB (NF-κB) and STAT3. On the other hand, p53 stimulates actin cytoskeleton remodeling and integrin-related signaling cascades. Here, we examined the p53-mediated link between regulation of the actin cytoskeleton and activation of NF-κB and STAT3 in MCF-7 cells and mouse embryonic fibroblasts (MEFs). In the absence of p53, STAT3 was constitutively activated. This activation was attenuated by depleting the expression of p65, a component of NF-κB. Integrin β3 expression and lamellipodia formation were also downregulated by NF-κB depletion. Inhibition of integrin αvβ3, Rac1 or Arp2/3, which diminished lamellipodia formation, suppressed STAT3 activation induced by p53 depletion. These results suggest that loss of p53 leads to STAT3 activation via NF-κB-dependent lamellipodia formation. Our study proposes a novel role for p53 in modulating the actin cytoskeleton through suppression of NF-κB, which restricts STAT3 activation.
Insights
Loss of tumor suppressor p53 activates STAT3 signaling. This occurs through nuclear factor-κB (NF-κB)-dependent actin cytoskeleton remodeling, highlighting p53
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Tumor suppressor p53 inhibits tumorigenesis by suppressing transcription factors like nuclear factor-κB (NF-κB) and STAT3.
- p53 also promotes actin cytoskeleton remodeling and integrin signaling.
Purpose of the Study:
- To investigate the link between p53, actin cytoskeleton regulation, and NF-κB/STAT3 activation in MCF-7 cells and mouse embryonic fibroblasts (MEFs).
Main Methods:
- Examined p53-mediated regulation of actin cytoskeleton and NF-κB/STAT3 signaling.
- Utilized p65 depletion, integrin αvβ3, Rac1, and Arp2/3 inhibition.
- Assessed STAT3 activation and lamellipodia formation in p53-deficient cells.
Main Results:
- Constitutive STAT3 activation was observed in p53-absent cells.
- Depleting p65 (an NF-κB component) attenuated STAT3 activation and downregulated integrin β3 and lamellipodia formation.
- Inhibiting integrin αvβ3, Rac1, or Arp2/3 suppressed STAT3 activation induced by p53 loss.
Conclusions:
- Loss of p53 promotes STAT3 activation via NF-κB-dependent lamellipodia formation.
- p53 plays a novel role in regulating the actin cytoskeleton by suppressing NF-κB, thereby limiting STAT3 activation.
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