Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis

Tang, Yilang; Reißig, Sonja; Glasmacher, Elke; Regen, Tommy; Wanke, Florian; Nikolaev, Alexei; Gerlach, Katharina; Popp, Vanessa; Karram, Khalad; Fantini, Massimo; Schattenberg, Jörn M.; Galle, Peter R.; Neurath, Markus F.; Weigmann, Benno; Kurschus, Florian C.; Hövelmeyer, Nadine; Waisman, Ari

doi:10.1053/j.gastro.2018.10.023

Cited by 29 publications

(25 citation statements)

References 50 publications

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“…Stained slides were examined and scored blindly by a pathologist without recognition of patients’ clinical data. Positive expression was assigned when evident cytoplasmic and/or nuclear staining was found 15,16 . The percentage of the positive cells was subjectively assessed at 200× magnification field.…”

Section: Methodsmentioning

confidence: 99%

Smad7 in psoriasis vulgaris patients: A clinical and immunohistochemical study

Hemida

Hammam

Salman

et al. 2020

J of Cosmetic Dermatology

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Background Psoriasis is an inflammatory disease that is mostly immune‐derived. It causes proliferation of skin cells, forming plaques. Psoriasis etiology is unknown. It might be multifactorial. Aims This work aimed to study Smad7 expression in psoriasis vulgaris patients in comparison with normal skin. Patients/Methods Thirty patients with psoriasis vulgaris in comparison with 20 age‐ and sex‐matched seemingly healthy individuals were selected. We used psoriasis area and severity index (PASI) to evaluate psoriasis severity. Skin biopsies were prepared from skin lesions (30), perilesions (30) and control (20) groups for histopathological and immunostaining evaluation of Smad7. Results Smad7 was progressively upregulated in proliferating keratinocytes from controls (58.18 ± 30.93) to perilesional (106 ± 38.93) and lesional (156.33 ± 62.01) skin (P < .001). Also, dermal inflammatory cells showed upregulation of Smad7 expression from control skin (40 ± 28.28) to skin lesions (137.33 ± 73.86) (P < .010). Smad7 expression showed a positive significant correlation with psoriasis severity (r = .452; P < .012). Conclusion Smad7 may be involved in increased keratinocyte proliferation as well as skin inflammation in psoriasis vulgaris patients.

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Section: Methodsmentioning

confidence: 99%

Smad7 in psoriasis vulgaris patients: A clinical and immunohistochemical study

Hemida

Hammam

Salman

et al. 2020

J of Cosmetic Dermatology

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“…In this context, it has been recently shown that a short natural splice form of the deubiquitinating enzyme CYLD (sCYLD), a tumour suppressor that is mutated in patients with familial cylindromatosus, interacts with Smad7 in the nucleus of CD mucosal T cells, where the complex inhibits the binding of Smad3 to the DNA, thereby abrogating TGF-β activity. (22) Enhanced expression of Smad7 in the initial, histological phases of CD could have important implications for the propagation of the in ammatory events, which lead to the development of the endoscopic recurrence. This hypothesis is supported by the demonstration that Smad7 expression in T cells correlates with disease severity in patients with CD (22) and mice overexpressing sCYLD and Smad7 develop spontaneous colitis due to altered TGF-β signalling and mediated by excessive activation of effector T cells.…”

Section: Discussionmentioning

confidence: 99%

“…(22) Enhanced expression of Smad7 in the initial, histological phases of CD could have important implications for the propagation of the in ammatory events, which lead to the development of the endoscopic recurrence. This hypothesis is supported by the demonstration that Smad7 expression in T cells correlates with disease severity in patients with CD (22) and mice overexpressing sCYLD and Smad7 develop spontaneous colitis due to altered TGF-β signalling and mediated by excessive activation of effector T cells. (22) These later ndings support and expand on data of our previous studies showing that inhibition of Smad7 in the gut of mice with experimental colitis restores TGF-β signalling thus suppressing cytokine responses and limiting the ongoing colitis.…”

Section: Discussionmentioning

confidence: 99%

High Smad7 in the early post-operative recurrence of Crohn’s disease

Zorzi¹,

Calabrese²,

Fusco³

et al. 2020

Preprint

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Background In Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD. Methods Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry. Results Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells. Conclusions Smad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.

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“…In this context, it has been recently shown that a short natural splice form of the deubiquitinating enzyme CYLD (sCYLD), a tumour suppressor that is mutated in patients with familial cylindromatosus, interacts with Smad7 in the nucleus of CD mucosal T cells, where the complex inhibits the binding of Smad3 to the DNA, thereby abrogating TGF-b activity. (23) Enhanced expression of Smad7 in the initial, histological phases of CD could have important implications for the propagation of the in ammatory events, which lead to the development of the endoscopic recurrence. This hypothesis is supported by the demonstration that Smad7 expression in T cells correlates with disease severity in patients with CD (23) and mice overexpressing sCYLD and Smad7 develop spontaneous colitis due to altered TGF-b signalling and mediated by excessive activation of effector T cells.…”

Section: Discussionmentioning

confidence: 99%

High Smad7 in the early post-operative recurrence of Crohn’s disease

Zorzi¹,

Calabrese²,

Fusco³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: In Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD. Methods: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry. Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-g-secreting cells. Conclusions: Smad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.

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Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis

Cited by 29 publications

References 50 publications

Smad7 in psoriasis vulgaris patients: A clinical and immunohistochemical study

Smad7 in psoriasis vulgaris patients: A clinical and immunohistochemical study

High Smad7 in the early post-operative recurrence of Crohn’s disease

High Smad7 in the early post-operative recurrence of Crohn’s disease

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