SnoN residue (1–366) attenuates hypertrophic scars through resistance to transforming growth factor-β1-induced degradation

Sun, Guifang; Li, Hongchang; Zhan, Yueping; Zhang, Xiaofen; Pan, Li-yun; Chen, Yafeng; Xu, Ke; Feng, Dan

doi:10.1038/s41374-019-0302-1

Cited by 6 publications

(3 citation statements)

References 48 publications

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“…In the process of tissue fibrosis, TGF‐β1 binds TGFBRII, which binds TGFBRI, which phosphorylates Smad2/3, which bind Smad 4 and translocate to the nucleus and bind Smad binding elements in gene promoters 35 . A growing body of research demonstrated that inhibiting the TGF‐β1/Smad2/3 pathway could efficiently reverse the pathological phenotypes of HFBs, 36,37 which is consistent with our research. Our study revealed that BMS‐202 attenuated pathological phenotypes of HFBs by regulating canonical TGF‐β1 signaling pathway as the C terminal phosphorylation of Smad2/3 in HFBs was significantly suppressed after BMS‐202 treatment.…”

Section: Resultssupporting

confidence: 89%

BMS‐202, a PD‐1/PD‐L1 inhibitor, decelerates the pro‑fibrotic effects of fibroblasts derived from scar tissues via ERK and TGFβ1/Smad signaling pathways

Cai

Xiao

et al. 2022

Immunity Inflam & Disease

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Introduction: Hypertrophic scar (HS), a fibroproliferative disorder of the skin with some tumor-like properties, is closely related to dysregulated inflammation. PD-1/PD-L1 inhibitor is a promising medication for cancer therapy as its potent functions on adaptive immune response; whether it could be a candidate for HS therapy has aroused our interest. This study aimed to explore the effect and the mechanism of BMS-202, a PD-1/PD-L1 inhibitor, in HS. Methods: Ten HS and adjacent normal skin tissues collected from HS patients were used to detect α-SMA, collagen I, and PD-L1 expression by Quantitative reverse transcription-polymerase chain reaction and western blot (WB) analysis. Fibroblasts derived from HS tissues (HFBs) were exposed to diverse concentrations of BMS-202, of which proliferation, migration, apoptosis, and collagen synthesis were evaluated by Cell Counting Kit-8, wound healing, terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End labeling, and [ 3 H]-proline incorporation assays, respectively. The effect of BMS-202 on α-SMA and collagen I expression, and transforming growth factor beta 1 (TGFβ1)/Smad signaling in HFBs was also determined by WB and enzyme-linked immunosorbent assay.Results: The expression level of PD-L1 was significantly elevated in both HS tissues and HFBs, which was positively correlated with α-SMA and collagen I expressions. BMS-202 exerted a significant suppression effect on the cell proliferation, migration, collagen synthesis, and α-SMA and collagen I expression of HFBs in a concentration-dependent way; but did not affect apoptosis. Finally, BMS-202 could reduce the phosphorylation of ERK1/2, Smad2, and Smad3, and the TGFβ1 expression once its concentration reached 2.5 nM. Conclusion:BMS-202 effectively suppressed proliferation, migration, and extracellular matrix deposition of HFBs, potentially through the regulation of the ERK and TGFβ1/Smad signaling pathways.

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Section: Resultssupporting

confidence: 89%

BMS‐202, a PD‐1/PD‐L1 inhibitor, decelerates the pro‑fibrotic effects of fibroblasts derived from scar tissues via ERK and TGFβ1/Smad signaling pathways

Cai

Xiao

et al. 2022

Immunity Inflam & Disease

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“…24–26 The hyperactive TGFβ1/Smad signaling leads to fibroblast proliferation, induces transformation of fibroblasts to myofibroblasts, increases collagen synthesis, inhibits matrix degradation, and eventually leads to hypertrophic scar formation. 27–30…”

Section: Discussionmentioning

confidence: 99%

“…[24][25][26] The hyperactive TGFβ1/Smad signaling leads to fibroblast proliferation, induces transformation of fibroblasts to myofibroblasts, increases collagen synthesis, inhibits matrix degradation, and eventually leads to hypertrophic scar formation. [27][28][29][30] Numerous studies have demonstrated that the ubiquitin-proteasome pathway regulates intracellular protein degradation and affects TGFβ1/ Smad signal transduction. 31,32 Deubiquitination is the reverse process of ubiquitination, which is mediated by deubiquitinating enzymes and plays an essential role in regulating the activity of TGFβ1/Smad signaling.…”

Section: Discussionmentioning

confidence: 99%

USP15 Enhances the Proliferation, Migration, and Collagen Deposition of Hypertrophic Scar–Derived Fibroblasts by Deubiquitinating TGF-βR1 In Vitro

Lin

Huang

et al. 2021

Plastic &Amp; Reconstructive Surgery

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Background: Hypertrophic scar is a fibroproliferative disorder caused by skin injury. The incidence of hypertrophic scar following trauma or burns is 40 to 70 percent or 70 percent, respectively. It has been shown that transforming growth factor (TGF) β1/Smad signaling plays a crucial role in hypertrophic scar, and that USP15 can regulate the activity of TGFβ1/Smad signaling to affect the progression of the disease. However, the underlying mechanism of USP15 in hypertrophic scar remains unclear. The authors hypothesized that USP15 was up-regulated and enhanced the proliferation, migration, invasion, and collagen deposition of hypertrophic scar–derived fibroblasts by deubiquitinating TGF-β receptor I (TβRI) in vitro. Methods: Fibroblasts were isolated from human hypertrophic scars in vitro. The knockdown and overexpression of USP15 in hypertrophic scar–derived fibroblasts were performed using lentivirus infection. The effect of USP15 on hypertrophic scar–derived fibroblast proliferation, migration, and invasion, and the expression of TβRI , Smad2 , Smad3 , α- SMA , COL1 , and COL3 , were detected by Cell Counting Kit-8, scratch, invasion, quantitative real-time polymerase chain reaction, and Western blot assays. The interaction between USP15 and TβRI was detected by co-immunoprecipitation and ubiquitination assays. Results: The authors demonstrated that USP15 knockdown significantly inhibited the proliferation, migration, and invasion of hypertrophic scar–derived fibroblasts in vitro and down-regulated the expression of TβRI , Smad2 , Smad3 , α- SMA , COL1 , and COL3 ; in addition, USP15 overexpression showed the opposite trends ( p < 0.05). Co-immunoprecipitation and ubiquitination assays revealed that USP15 interacted with TβRI and deubiquitinated TβRI. Conclusion: USP15 enhances the proliferation, migration, invasion, and collagen deposition of hypertrophic scar–derived fibroblasts by deubiquitinating TβRI in vitro.

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The Ubiquitin Proteasome System and Skin Fibrosis

Shen

Zhang

et al. 2021

Mol Diagn Ther

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SnoN residue (1–366) attenuates hypertrophic scars through resistance to transforming growth factor-β1-induced degradation

Cited by 6 publications

References 48 publications

BMS‐202, a PD‐1/PD‐L1 inhibitor, decelerates the pro‑fibrotic effects of fibroblasts derived from scar tissues via ERK and TGFβ1/Smad signaling pathways

BMS‐202, a PD‐1/PD‐L1 inhibitor, decelerates the pro‑fibrotic effects of fibroblasts derived from scar tissues via ERK and TGFβ1/Smad signaling pathways

USP15 Enhances the Proliferation, Migration, and Collagen Deposition of Hypertrophic Scar–Derived Fibroblasts by Deubiquitinating TGF-βR1 In Vitro

The Ubiquitin Proteasome System and Skin Fibrosis

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