Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour necrosis factor-alpha (TNF-alpha) is a key mediator of inflammation in host defence against infection and in autoimmune disease. Its production is controlled post-transcriptionally by multiple RNA-binding proteins that interact with the TNF-alpha AU-rich element and regulate its expression; one of these is Fragile X mental retardation-related protein 1 (FXR1). The anti-inflammatory cytokine transforming growth factor-beta1 (TGF-beta1), which is involved in the homeostatic regulation of TNF-alpha, causes post-transcriptional suppression of lipopolysaccharide (LPS)-induced TNF-alpha production. We report here that this depends on FXR1. Using RAW 264.7 cells and bone marrow-derived macrophages (BMDMphi) stimulated with LPS and TGF-beta1, we show that TGF-beta1 inhibits TNF-alpha protein secretion, whereas TNF-alpha mRNA expression remains unchanged. This response is recapitulated by the 3'-UTR of TNF-alpha, which is known to bind FXR1. TGF-beta1 induces FXR1 with a pattern of expression distinct from that of tristetraprolin, T-cell intracellular antigen 1, or human antigen R. When FXR1 is knocked down, TGF-beta1 is no longer able to inhibit LPS-induced TNF-alpha protein production, and overexpression of FXR1 suppresses LPS-induced TNF-alpha protein production. Targeting the p38 mitogen-activated protein kinase pathway of LPS-treated cells with small molecule inhibitors can induce FXR1 protein and mRNA expression. In summary, TGF-beta1 opposes LPS-induced stabilization of TNF-alpha mRNA and reduces the amount of TNF-alpha protein, through induction of expression of the mRNA-binding protein FXR1.
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PMID:Fragile X-related protein FXR1 controls post-transcriptional suppression of lipopolysaccharide-induced tumour necrosis factor-alpha production by transforming growth factor-beta1. 2049 1

Fragile X mental retardation-related protein 1 (FXR1) is a cytoplasmic RNA-binding protein highly conserved among vertebrates. It has been studied for its role in muscle development, inflammation, and tumorigenesis, being related, for example, to metastasizing behavior in human and canine uveal melanoma. Anti-FXR1 antibodies have never been validated in the canine species. To investigate FXR1 expression in canine melanocytic tumors, the present study tested two commercially available polyclonal anti-human FXR1 antibodies, raised in goat and rabbit, respectively. The cross-reactivity of the anti-FXR1 antibodies was assessed by Western blot analysis, and the protein was localized by IHC in a set of normal canine tissues and in canine melanocytic tumors (10 uveal and 10 oral). Western blot results demonstrated that the antibody raised in rabbit specifically recognized the canine FXR1, while the antibody raised in goat did not cross-react with this canine protein. FXR1 protein was immunodetected using rabbit anti-FXR1 antibody, in canine normal tissues with different levels of intensity and distribution. It was also detected in 10/10 uveal and 9/10 oral melanocytic tumors. The present study validated for the first time the use of anti-FXR1 antibody in dogs and highlighted different FXR1 protein expression in canine melanocytic tumors, the significance of which is undergoing further investigations.
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PMID:Immunohistochemical Expression of FXR1 in Canine Normal Tissues and Melanomas. 2960 6