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.

Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

“…CXCR2 is important in the pathology of a wide diversity of chronic pulmonary diseases, and the modulation of CXCR2 function is considered as a possible therapeutic strategy [54] . Interestingly, blocking of these GPCRs prior to mycobacterial infection repealed the mycobacteria-induced actin redistribution and suppression of epithelial NF-κB and c-Jun, further supporting the theory that mycobacteria utilize GPCRs to manipulate cellular signalling [23] . GPCRs are also required for the activation of STAT, and STAT1 mutations were recently identified in patients with disseminated BCG infection [55,56] .…”

“…Inhibition of Rac1 was recently shown to abolish tumour protein p53 suppression of the transcription factors STAT and NF-κB [23] . We investigated the mycobacterial influence on epithelial p53 with a phosphorylation assay ( Fig.…”

“…These low-molecular-weight proteins belong to the Ras GTPase superfamily and include Rab and Rho/Rac, with the ability to act as molecular switches by coupling extracellular signals to different cellular responses, cytoskeletal integrity, intracellular vesicular transport, and trafficking of proteins [22] . Inhibition of Rac1 was recently shown to repeal tumour protein p53 suppression of STAT and NF-κB, and Rho is essential in the establishment and maintenance of tight junctions [23] . Previous studies indicate that signalling through TLRs is important for the phagocytosis of bacteria, as TLR-mediated MyD88-dependent activation of p38 is required for phagosome maturation [24,25] .…”

The Ins and Outs of Small GTPase Rac1 in the Vasculature

“…In embryonic fibroblasts, tumor suppressor p53 stimulates actin cytoskeleton remodeling and limits lamellipodia formation, since in the absence of p53 these features were disturbed and migration was induced. P53 depletion induced STAT3, and inhibition of Rac1, actin-related protein 2/3, or NF-kB suppressed STAT3 and diminished lamellipodia formation (Guo et al, 2014). In addition, a role for STAT3 independent of its transcriptional activity was found.…”

Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway

“…Tip60 directly interacts and acetylates p53, and thus modulates its stability and transcriptional activity. Loss of p53 function results in the constitutive activation of NF-κB [28,29]. Knockdown of Tip60 down-regulates the expression of p21 which is a target gene of p53 (Fig.…”