Mechanisms of transforming growth factor β<sub>1</sub>
/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts

He, Songqing; Liu, X.; Yang, Yan; Huang, Weijuan; Xu, Suowen; Yang, Sen; Zhang, X.; Roberts, Michael S.

doi:10.1111/j.1365-2133.2009.09511.x

Cited by 98 publications

(76 citation statements)

References 39 publications

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“…It has been demonstrated that Smad4 deletions are associated with pancreatic cancer metastasis, and Smad4 gene mutations are associated with poor prognosis in pancreatic cancer (1,2). Previous studies have established that Smad4 may interact with other signaling pathways, including Notch and MAPK, and function independently of TGF-β (20). Despite clear evidence of the association between Smad4 and pancreatic cancer (1,(4)(5)(6), the mechanism of the cross-talk between Smad4 and other signaling pathways that affect the development of pancreatic cancer remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have revealed that the Smad signaling pathway downstream of TGF-β has complicated interactions with MAPK members, including p38, JNK and extracellular signal-regulated kinases (ERKs) (19,20). Previous studies conducted over the past decade have revealed that the Smad2/3 complex is phosphorylated by JNK and p38 through direct or indirect ways; and this complex subsequently binds to Smad4, thus regulating downstream gene transcription (20). However, little is known regarding whether Smad4 regulates JNK and p38, and whether it affects the occurrence, development and metastasis of tumors.…”

Section: Introductionmentioning

confidence: 99%

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Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Zhang¹,

Cao²,

Pei³

et al. 2016

Oncology Letters

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Abstract. Smad4 is a common Smad and is a key downstream regulator of the transforming growth factor-β signaling pathway, in which Smad4 often acts as a potent tumor suppressor and functions in a highly context-dependent manner, particularly in pancreatic cancer. However, little is known regarding whether Smad4 regulates other signaling pathways involved in pancreatic cancer. The present study demonstrated that Smad4 downregulates c-Jun N-terminal kinase (JNK) activity using a Smad4 loss-of-function or gain-of-function analysis. Additionally, stable overexpression of Smad4 clearly affected the migration of human pancreatic epithelioid carcinoma PANC-1 cells, but did not affect cell growth. In addition, the present study revealed that upregulation of mitogen-activated protein kinase phosphatase-1 is required for the reduction of JNK activity by Smad4, leading to a decrease in vascular endothelial growth factor expression and inhibiting cell migration. Overall, the present findings indicate that Smad4 may suppress JNK activation and inhibit the tumor characteristics of pancreatic cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Zhang¹,

Cao²,

Pei³

et al. 2016

Oncology Letters

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“…It has been widely accepted that the dysregulation of the TGF-β/Smad pathway plays a key role in hypertrophic or keloid scar formation in human skin tissues. A number of studies have clearly demonstrated that the increased expression of TGF-β receptors (types I and II) and the increased phosphorylation of Smad3 in keloid fibroblasts compared to normal HSFs, as well as the suppression of the TGF-β1/Smad pathway by certain chemicals such as curcumin, may exert chemopreventive effects, thus preventing keloid formation (7)(8)(9).…”

Section: Discussionmentioning

confidence: 99%

“…Receptor-activated Smads (R-Smads; Smad2 and Smad3) are the key intracellular components in the TGF-β1 signaling pathway involved in the production of type I collagen. Thus, the dysregulation of the TGF-β1/Smad pathway is crucial for the pathogenesis of hypertrophic and keloid scar formation (7,8).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of type I collagen expression in silibinin-treated human skin fibroblasts by blocking the activation of Smad2/3-dependent signaling pathways: Potential therapeutic use in the chemoprevention of keloids

Cho

Lee

2013

International Journal of Molecular Medicine

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Abstract. The inhibition of the Smad2/3 pathway is a key step involved in the downregulation of type I collagen synthesis, thus preventing keloid formation in tissue. In this study, we investigated the effect of silibinin on the proliferation of human skin fibroblasts (HSFs), as well as its effect on the expression of type I collagen, matrix metalloproteinase (MMP)-1, Smad2 and Smad3. Our results showed that the proliferation rates of the fibroblasts were not markedly decreased in a dose-and time-dependent manner following treatment with silibinin. Even though silibinin did not exert any cytotoxic effects on HSFs, the expression of type I collagen was markedly decreased in a dose-and time-dependent manner in the silibinin-treated HSFs. Consistent with this finding, the decreased promoter activity of type I collagen was observed in the HSFs following treatment with silibinin. The MMP-1 and MMP-2 expression levels were increased in the silibinin-treated HSFs. Moreover, the silibinin-induced downregulation of type I collagen was associated with the inhibition of Smad2/3 activation in the transforming growth factor-β1 (TGF-β1)-treated HSFs. We further demonstrated that silibinin attenuated the translocation of Smad2 and Smad3 to the nucleus in the TGF-β1-treated HSFs. Taken together, our data indicate that silibinin has the potential to prevent fibrotic skin changes by inducing the downregulation of type I collagen expression; this effect was partly mediated by the inhibition of the Smad2/3-dependent signaling pathway in HSFs.

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“…По мнению ряда авторов, фосфорилирование MAPK (ERK1/2, p38, JNK) под воздействием трансформирующего фактора роста β1 играет роль в патогенезе развития ги-пертрофического кожного рубца [34][35][36][37].…”

Section: марк как потенциальные регуляторы роста соединительной тканиunclassified

Influence on mitogen-activated protein kinases as a new direction of connective tissue growth regulation

Shurygina¹,

Шурыгин²,

Зеленин³

et al. 2017

Bûll. sib. med.

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В настоящее время распространенность па-тологий, при которых избыточный рост соеди-нительной ткани является одним из основных факторов патогенеза (кардиосклероз и связанная с ним сердечная недостаточность, контрактуры суставов, спаечная болезнь, пневмосклероз, цир-УДК 611-018.2:577.112 DOI: 10.20538/1682DOI: 10.20538/ -0363-2017 Для цитирования: Шурыгина И.А., Шурыгин М.Г., Зеленин Н.В., Аюшинова Н.И. Воздействие на митогенактивируемые протеинкиназы как новое направление регуляции роста соединительной ткани. Бюллетень сибирской медицины. 2017; 16 (4): 86-93.Воздействие на митогенактивируемые протеинкиназы как новое направление регуляции роста соединительной ткани Шурыгина И.А., Шурыгин М.Г., Зеленин В.Н., Аюшинова Н.И. Россия, 664003, г. Иркутск, ул. Борцов Революции, 1 РЕЗЮМЕ В обзоре представлена современная классификация, функции основных групп митогенактивируемых протеинкиназ (МАРК). Приведены данные о путях их активации и функционирования. Основное вни-мание уделено семейству р38 МАРК. В обзоре воздействие на данные сигнальные каскады рассмотрено как перспективное направление воздействия на рост соединительной ткани. В этом аспекте обобщен мировой опыт по активации и блокаде внутриклеточных каскадов. Обобщен собственный опыт работы в данном направлении. В частности продемонстрировано, что стимуляция р38 МАРК при подавлении активности JNK каскада ведет к ускоренному образованию соединительной ткани в зоне послеопера-ционного хирургического рубца, доказана возможность управления ростом соединительной ткани при воздействии на МАР-киназные каскады. Пролонгированная блокада р38 МАРК снижает ширину кожно-го рубца и плотность коллагеновых волокон в зоне формирования послеоперационного рубца, снижает интенсивность спайкообразования в брюшной полости при травме брюшины. Иркутский научный центр хирургии и травматологии (ИНЦХТ)Таким образом, учитывая важную роль и универсальность МАР-киназных механизмов регуляции кле-точного роста и дифференцировки, перспективно изучение участия данных механизмов в универсаль-ных биологических процессах, таких как воспаление, апоптоз, регенерация, а также разработка на этой основе способов управления течением этих процессов. Использование стимуляторов и блокаторов МАР-киназных механизмов перспективно как новое направление в лечении многих заболеваний, патоге-нез которых связан с нарушением клеточной дифференцировки, пролиферации, избыточной выработки цитокинов, управлением ростом соединительной ткани.Ключевые слова: митогенактивируемая протеинкиназа, р38 МАРК, JNK MAPK, ERK МАРК, инги-битор МАРК, соединительная ткань.

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Mechanisms of transforming growth factor β₁ /Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts

Abstract: These results suggested that the ERK, JNK and p38 pathways mediate TGF-beta(1)/Smad signal transduction and might be considered as specific targets of drug therapy for keloids.

Cited by 98 publications

References 39 publications

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Downregulation of type I collagen expression in silibinin-treated human skin fibroblasts by blocking the activation of Smad2/3-dependent signaling pathways: Potential therapeutic use in the chemoprevention of keloids

Influence on mitogen-activated protein kinases as a new direction of connective tissue growth regulation

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Mechanisms of transforming growth factor β1 /Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts

Abstract: These results suggested that the ERK, JNK and p38 pathways mediate TGF-beta(1)/Smad signal transduction and might be considered as specific targets of drug therapy for keloids.

Cited by 98 publications

References 39 publications

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Downregulation of type I collagen expression in silibinin-treated human skin fibroblasts by blocking the activation of Smad2/3-dependent signaling pathways: Potential therapeutic use in the chemoprevention of keloids

Influence on mitogen-activated protein kinases as a new direction of connective tissue growth regulation

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Mechanisms of transforming growth factor β₁ /Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts