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AMAP1 as a negative-feedback regulator of nuclear factor-?B under inflammatory conditions.

ABSTRACT: NF-?B is a major transcriptional factor regulating many cellular functions including inflammation; therefore, its appropriate control is of high importance. The detailed mechanism of its activation has been well characterized, but that of negative regulation is poorly understood. In this study, we showed AMAP1, an Arf-GTPase activating protein, as a negative feedback regulator for NF-?B by binding with IKK?, an essential kinase in NF-?B signaling. Proteomics analysis identified AMAP1 as a binding protein with IKK?. Overexpression of AMAP1 suppressed NF-?B activity by interfering the binding of IKK? and NEMO, and deletion of AMAP1 augmented NF-?B activity. The activation of NF-?B induced translocation of AMAP1 to cytoplasm from cell membrane and nucleus, which resulted in augmented interaction of AMAP1 and IKK?. These results demonstrated a novel role of AMAP1 as a negative feedback regulator of NF-?B, and presented it as a possible target for anti-inflammatory treatments.

SUBMITTER: Tien DN

PROVIDER: S-EPMC4035583 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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AMAP1 as a negative-feedback regulator of nuclear factor-κB under inflammatory conditions.

Tien Dat Nguyen DN Kishihata Masako M Yoshikawa Ayumu A Hashimoto Ari A Sabe Hisataka H Nishi Eiichiro E Kamei Kaeko K Arai Hidenori H Kita Toru T Kimura Takeshi T Yokode Masayuki M Ashida Noboru N

Scientific reports 20140528

NF-κB is a major transcriptional factor regulating many cellular functions including inflammation; therefore, its appropriate control is of high importance. The detailed mechanism of its activation has been well characterized, but that of negative regulation is poorly understood. In this study, we showed AMAP1, an Arf-GTPase activating protein, as a negative feedback regulator for NF-κB by binding with IKKβ, an essential kinase in NF-κB signaling. Proteomics analysis identified AMAP1 as a bindin ...[more]

PMID: 24865276

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Project description:BackgroundVascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.MethodsWe use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis.ResultsWe demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy.ConclusionsLMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.

Dataset Information

AMAP1 as a negative-feedback regulator of nuclear factor-?B under inflammatory conditions.

Publications

AMAP1 as a negative-feedback regulator of nuclear factor-κB under inflammatory conditions.

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