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C18 ORF1, a novel negative regulator of transforming growth factor-? signaling.

ABSTRACT: Transforming growth factor (TGF)-? signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-? signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-? signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-? signaling but not bone morphogenetic protein signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with the Smad anchor for receptor activation for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-? type I receptor (also termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-?-induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-?. Consistently, TGF-?-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-? signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-? signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-? signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF-? signaling in a coordinated manner when cells are stimulated with high levels of TGF-?.

SUBMITTER: Nakano N

PROVIDER: S-EPMC4007458 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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C18 ORF1, a novel negative regulator of transforming growth factor-β signaling.

Nakano Naoko N Maeyama Kota K Sakata Nobuo N Itoh Fumiko F Akatsu Ryosuke R Nakata Miki M Katsu Yuki Y Ikeno Souichi S Togawa Yoko Y Vo Nguyen Thanh Thao TT Watanabe Yukihide Y Kato Mitsuyasu M Itoh Susumu S

The Journal of biological chemistry 20140313 18

Transforming growth factor (TGF)-β signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-β signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-β signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs ...[more]

PMID: 24627487

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Project description:BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor ? (TGF-?) 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-?1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We 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. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-? in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-? 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-? treatment. TGF-? neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-? signaling by inducing expression of Tgfb1 mRNA, TGF-? protein, ?v and ?3 integrins that promote activation of latent TGF-?, 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-? 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. CONCLUSIONS:LMO7 is induced by TGF-? and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-? pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.

Dataset Information

C18 ORF1, a novel negative regulator of transforming growth factor-? signaling.

Publications

C18 ORF1, a novel negative regulator of transforming growth factor-β signaling.

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