Background & Aims: Transforming growth factor (TGF)-beta 1 is one of the most powerful endogenous negative regulators of inflammation. In patients with inflammatory bowel disease, despite abundant local TGF-beta 1, there is a failure of TGF-beta-mediated negative regulation of nuclear factor kappa B activation and proinflammatory cytokine production because of increased intracellular expression of the endogenous inhibitor of TGF-beta 1 signaling, Smad7. In this study, we examined the molecular mechanism underlying the induction of Smad7 in the human gut. Methods: Whole intestinal mucosal and lamina propria mononuclear cell samples were analyzed for Smad7 by real-time polymerase chain reaction and Western blotting. Smad7 ubiquitination and acetylation, and interaction of Smad7 with the intrinsic histone acetyltransferase, p300, were examined by immunoprecipitation and Western blotting. The effect of p300 silencing on Smad7 expression was determined in Crohn's disease lamina propria mononuclear cells. Results: We showed that Smad7 is not transcriptionally regulated in human gut but that its increase in patients with inflammatory bowel disease is due to posttranscriptional acetylation and stabilization by p300, which prevents Smad7 ubiquitination and degradation in the proteasome. Hence, Smad7 protein in cells from normal gut is ubiquitinated and rapidly degraded. In contrast, in inflamed gut, Smad7 is acetylated and not ubiquitinated, is not degraded, and can be decreased by short interfering RNA to p300. Conclusions: These results identify posttranslational protein modification as of importance in chronic gut inflammation in humans.

Monteleone, G., DEL VECCHIO BLANCO, G., Monteleone, I., Fina, D., Caruso, R., Gioia, V., et al. (2005). Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. GASTROENTEROLOGY, 129(5), 1420-1429 [10.1053/j.gastro.2005.09.005].

Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease

MONTELEONE, GIOVANNI;DEL VECCHIO BLANCO, GIOVANNA;MONTELEONE, IVAN;FEDERICI, GIORGIO;BERNARDINI, SERGIO;PALLONE, FRANCESCO;
2005-01-01

Abstract

Background & Aims: Transforming growth factor (TGF)-beta 1 is one of the most powerful endogenous negative regulators of inflammation. In patients with inflammatory bowel disease, despite abundant local TGF-beta 1, there is a failure of TGF-beta-mediated negative regulation of nuclear factor kappa B activation and proinflammatory cytokine production because of increased intracellular expression of the endogenous inhibitor of TGF-beta 1 signaling, Smad7. In this study, we examined the molecular mechanism underlying the induction of Smad7 in the human gut. Methods: Whole intestinal mucosal and lamina propria mononuclear cell samples were analyzed for Smad7 by real-time polymerase chain reaction and Western blotting. Smad7 ubiquitination and acetylation, and interaction of Smad7 with the intrinsic histone acetyltransferase, p300, were examined by immunoprecipitation and Western blotting. The effect of p300 silencing on Smad7 expression was determined in Crohn's disease lamina propria mononuclear cells. Results: We showed that Smad7 is not transcriptionally regulated in human gut but that its increase in patients with inflammatory bowel disease is due to posttranscriptional acetylation and stabilization by p300, which prevents Smad7 ubiquitination and degradation in the proteasome. Hence, Smad7 protein in cells from normal gut is ubiquitinated and rapidly degraded. In contrast, in inflamed gut, Smad7 is acetylated and not ubiquitinated, is not degraded, and can be decreased by short interfering RNA to p300. Conclusions: These results identify posttranslational protein modification as of importance in chronic gut inflammation in humans.
2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/12 - GASTROENTEROLOGIA
English
antibiotic agent; azathioprine; benzyloxycarbonylleucylleucylleucinal; corticosteroid; histone acetyltransferase; mesalazine; mg 115; proteasome; proteasome inhibitor; protein p300; Smad7 protein; small interfering RNA; unclassified drug; acetylation; article; clinical article; colon resection; controlled study; Crohn disease; enteritis; human; human cell; human tissue; immunoprecipitation; intestine mucosa; lamina propria; mononuclear cell; priority journal; protein degradation; protein expression; protein induction; protein processing; protein protein interaction; protein stability; real time polymerase chain reaction; ubiquitination; Western blotting; Acetylation; Cell Cycle Proteins; Chronic Disease; Crohn Disease; Enteritis; Gene Expression Regulation; Histone Acetyltransferases; Humans; Proteasome Endopeptidase Complex; RNA Interference; RNA, Messenger; RNA, Small Interfering; Smad7 Protein; Transcription Factors; Transcription, Genetic; Ubiquitin
Monteleone, G., DEL VECCHIO BLANCO, G., Monteleone, I., Fina, D., Caruso, R., Gioia, V., et al. (2005). Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. GASTROENTEROLOGY, 129(5), 1420-1429 [10.1053/j.gastro.2005.09.005].
Monteleone, G; DEL VECCHIO BLANCO, G; Monteleone, I; Fina, D; Caruso, R; Gioia, V; Ballerini, S; Federici, G; Bernardini, S; Pallone, F; Macdonald, T...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/28786
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