The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

Li, Ping; Liu, Ping; Peng, Yan; Zhang, Zhuo-Hang; Li, Xiaoming; Xiong, Ranhua; Chen, Xing; Zhao, Yan; Ning, Yuping; Yang, Nan; Zhang, Bo; Zhou, Yuan‐Guo

doi:10.1080/15384101.2018.1480221

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…However, we observed a proportional reduction in both total and phosphorylated CREB by ErbB TKIs and the ERK inhibitor SCH772984, implicating that with chronic ErbB TKI treatment, the role of phosphorylated ERK involves maintaining CREB expression and phosphorylation, and this occurs at a post-translational level, given the unchanged CREB mRNA level, although the mechanism has not been determined. Notably, other publications did not observe a similar effect of ERK inhibitors on CREB expression (Fu et al, 2019;Li et al, 2018), a discrepancy which might be explained by the shorter period (maximum 24 hours) of exposure in those studies as compared to ours (6 days).…”

Section: Discussioncontrasting

confidence: 78%

Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway

Yang

Lin

Sarker

et al. 2020

Preprint

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Diarrhea is the major side effect of first- and second-generation ErbB tyrosine kinase inhibitors (TKI), the mechanism of which remains incompletely understood. The current studies were carried out over the time frame that ErbB TKIs usually initiate diarrhea. We report in Caco-2/bbe cells that exposure of ErbB TKIs, but not non-ErbB TKIs for six days at clinically-relevant concentrations significantly reduced the expression of DRA and inhibited apical Cl-/HCO3- exchange activity. The ErbB TKIs decreased DRA expression through an ERK/Elk-1/CREB/AP-1 dependent pathway. The blockade of ERK phosphorylation by ErbB TKIs decreased the phosphorylation of Elk-1 and the amount of total and p-CREB, and reduced the expression of C-Fos, which is part of the AP-1 complex that maintain DRA expression. Altogether, our studies demonstrate that ErbB TKIs decrease expression and activity of DRA, which occurs over the time frame that these drugs clinically cause diarrhea, and since DRA is part of the intestinal neutral NaCl absorptive process, the reduced absorption is likely to represent a major contributor to the ErbB TKI-associated diarrhea.

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Section: Discussioncontrasting

confidence: 78%

Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway

Yang

Lin

Sarker

et al. 2020

Preprint

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“…In addition to MITF degradation, the transcription of MITF was down-regulated by capsaicin in melanocytes. The inhibitory effect on MITF transcription, mediated by capsaicin, could possibly be due to the induction of SMAD2 through promoting expression of c-SKI, which then suppresses PAX3 expression. The declined level of PAX3 could lead to a decrease in transcription of MITF gene .…”

Section: Discussionmentioning

confidence: 99%

Capsaicin Inhibits the Expression of Melanogenic Proteins in Melanocyte via Activation of TRPV1 Channel: Identifying an Inhibitor of Skin Melanogenesis

Bai

Xia

et al. 2020

J. Agric. Food Chem.

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Chili pepper belongs to the genus Capsicum of Solanaceae family. Capsaicin is the primary capsaicinoid in placenta and flesh of chili pepper fruit, which has been shown to have various pharmacological functions, including gastric protection, anti-inflammation, and obesity treatment. Here, we revealed that capsaicin as well as chilli extract was able to inhibit synthesis of melanin in melanocytes. In cultured melanocytes, the melanin content was reduced to 54 ± 6.55% and 42 ± 7.41% with p < 0.001 under treatment of 50 μM capsaicin for 24 and 72 h, respectively. In parallel, the protein levels of tyrosinase and tyrosinase-related protein-1 were reduced to 62 ± 8.35% and 48 ± 8.92% with p < 0.001. Such an inhibitory effect of capsaicin was mediated by activation of transient receptor potential vanilloid 1-induced phosphorylation of extracellular signal-regulated kinase. This resulted in a degradation of microphthalmia-associated transcription factor, leading to reduction of melanogenic enzymes and melanin. These results revealed that capsaicin could be an effective inhibitor for skin melanogenesis. Hence, chili pepper, as our daily food, has potential in dermatological application, and capsaicin should be considered as a safe agent in treating hyperpigmentation problems.

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“…TGF-β1 can bypass the effects of the Smad2/3 signaling pathway on the E3 ubiquitin ligase Arkadia to mediate rapid c-Ski degradation 29 . In addition, c-Ski plays an essential role in the TGF-β1-mediated bidirectional regulation of primary fibroblast cell proliferation, as c-Ski expression is increased at low TGF-β1 concentrations and reduced at high TGF-β1 concentrations 7 , 30 . In addition, TGF-β1 is highly expressed in most human tumors 31 - 34 .…”

Section: Introductionmentioning

confidence: 99%

Ski mediates TGF-β1-induced fibrosarcoma cell proliferation and promotes tumor growth

Li¹,

Wang²,

Zhai³

et al. 2020

J. Cancer

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Background: TGF-β1 promotes cell proliferation in only some tumors and exerts bidirectional regulatory effects on the proliferation of fibroblasts. This study intends to explore whether the mechanism is related to increased expression of Ski. Methods: Cell proliferation of the fibrosarcoma cell line L929 was assessed with an ELISA BrdU kit. The mRNA and protein expression levels of the corresponding factors were measured by RT-qPCR, immunohistochemistry or Western blotting in vitro and in vivo. Additionally, c-Ski was knocked down using RNAi. The expression of Ski in human dermatofibrosarcoma protuberans (DFSP) specimens was measured by immunohistochemistry. Results: TGF-β1 promoted the continued proliferation of L929 cells in a dose-dependent manner, with increased c-Ski expression levels. Conversely, inhibition of c-Ski significantly abrogated this unidirectional effect, significantly inhibited the decrease in p21 protein levels and did not affect the increase in p-Smad2/3 levels upon TGF-β1 treatment. Similarly, inhibition of c-Ski significantly abrogated the growth-promoting effect of TGF-β1 on xenograft tumors. Furthermore, we found that high expression of Ski in DFSP was correlated with a low degree of tumor differentiation. Conclusions: Our data reveal that high c-Ski expression is a cause of TGF-β1-promoted proliferation in fibrosarcoma tumor cells and show that inhibiting Ski expression might be effective for treating tumors with high Ski levels.

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The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

Cited by 6 publications

References 34 publications

Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway

Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway

Capsaicin Inhibits the Expression of Melanogenic Proteins in Melanocyte via Activation of TRPV1 Channel: Identifying an Inhibitor of Skin Melanogenesis

Ski mediates TGF-β1-induced fibrosarcoma cell proliferation and promotes tumor growth

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