SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4

Bertrand-Chapel, Adrien; Caligaris, Cassandre; Fenouil, Tanguy; Savary, Clara; Aires, Sophie; Martel, Sylvie; Huchedé, Paul; Chassot, Christelle; Chauvet, Véronique; Cardot‐Ruffino, Victoire; Morel, Anne-Pierre; Subtil, Fabien; Mohkam, Kayvan; Mabrut, Jean‐Yves; Tonon, Laurie; Viari, Alain; Cassier, Philippe; Hervieu, Valérie; Castets, Marie; Mauviel, Alain; Sentis, Stéphanie; Bartholin, Laurent

doi:10.1038/s42003-022-03994-6

Cited by 25 publications

(16 citation statements)

References 73 publications

(74 reference statements)

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“…The initiation of TGF-β's signal transduction transpires through serine or threonine receptor kinases (Zhang et al, 2014). This leads to the phosphorylation of intracellular transducers Smad2/3, which subsequently form a complex with Smad4 (Bertrand-Chapel et al, 2022). This intricate assemblage traverses from the cell membrane into the nucleus, thereby eliciting a transcriptional response to TGF-β within the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Experimental Studies on the Effects of Glycitinregulated TGF-β Signaling Pathway on the Proliferation, Osteogenic, and Lipogenic Differentiation of BMSCs

Zhu,

Zhang,

Sun

et al. 2024

Pharmacognosy Magazine

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Background Glycitin, generated from the seeds of the legume soybean, has an essential function in antioxidant, obesity inhibition, and wound healing promotion. Furthermore, recent research has shown that it has anti-inflammatory and cartilage-protective properties. Objectives This study was designed to investigate the osteogenic effects of glycitin and the transforming growth factor-β (TGF-β) signaling pathway on bone marrow mesenchymal stem cells (BMSCs), as well as their interaction. Materials and Methods We isolated rabbit BMSCs by whole bone marrow adherent method and cultured, identified, and induced differentiation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to determine the proliferation ability of BMSCs with different concentrations of glycitin at different times; reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression levels of osteogenesis-related genes runt-related transcription factor 2 (Runx2), collagen type I (Col-1), and osteocalcin (OC) mRNA; and a kit was used to determine the activities of alkaline phosphatase and triglycerides (TG) in BMSCs. A Western blot was used to detect the expression of TGF-β protein in each group. Results On the fifth day of BMSC primary culture, the morphology of long spindle-shaped cells might be plentiful, dominated by a daisy-like or whirling arrangement. They proliferated rapidly and fused to 70%–80% on the eighth day of culture; the third generation of BMSCs was taken for phenotyping, and the detection results of flow cytometry analysis showed that the surface antigenic markers of BMSCs, CD44, and CD90 were positive, whereas CD34 and CD45 were negative; after osteogenic induction of BMSCs, visible calcified nodules were evident. There was cartilage matrix formation after osteogenic induction; glycitin promoted BMSC proliferation in a time-dependent and dose-dependent manner, and BMSC proliferation increased significantly at 20 µM glycitin for 3–5 days; glycitin increased the expression of Runx2, Col-1, and OC mRNA in BMSCs and increased the activity of alkaline phosphatase (ALP) while decreasing the activity of TG. Meanwhile, 20 µM glycitin dramatically increased the expression of TGF-β. Conclusion These findings imply that glycitin increases BMSCs proliferation and osteogenic differentiation. By regulating the TGF-β signaling pathway, glycitin modulates the differentiation of BMSCs into osteoblasts.

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Section: Discussionmentioning

confidence: 99%

Experimental Studies on the Effects of Glycitinregulated TGF-β Signaling Pathway on the Proliferation, Osteogenic, and Lipogenic Differentiation of BMSCs

Zhu,

Zhang,

Sun

et al. 2024

Pharmacognosy Magazine

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“…Additionally, it was shown that the depletion of CDCA5 resultedin a downregulation of the phosphorylation of Smad2/3. A study observed that the oncogenic effects of TGF-β can be mediated by Smad2/3 even when Smad4 is absent [ 31 ]. Unfortunately, the current study failed to elucidate the specific molecular mechanism, which will be the direction of thefuture research endeavors.…”

Section: Discussionmentioning

confidence: 99%

CDCA5 promoted cell invasion and migration by activating TGF-β1 pathway in human ovarian cancer cells

Zhang,

et al. 2024

J Ovarian Res

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Background The gene cell division cycle associated 5 (CDCA5), also called sororin, has oncogenic characteristics and is upregulated in various carcinomas. Nevertheless, the involvement of CDCA5 in ovarian cancer (OC), a highly aggressive form of cancer, and the underlying mechanism of metastasis remain inadequately investigated. Results The bioinformatics data revealed a negative correlation between the patient’s survival and CDCA5 expression, which was overexpressed in OC. Functional assays also confirmed high expression levels of CDCA5 in OC tissues and cells. This suggests that CDCA5 may potentially enhance the motility, migration, and proliferation of OC cells invitro. It impedes DNA damage and apoptosis in OC cells, inhibiting xenograft development in nude mice. The RNA sequencing results suggest CDCA5 is majorly associated with biological functions related to the extracellular matrix (ECM) and influences the transforming growth factor (TGF) signaling pathway. Moreover, subsequent functional investigations elucidated that CDCA5 facilitated the migration and invasion of OC cells viathe TGF-β1/Smad2/3 signaling pathway activation. Conclusions CDCA5 may be a strong potential therapeutic target for the treatment and management of OC.

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“…SMAD4 has been suggested as a central component of EMT transition in human colorectal cancer ( 45 ), but in absence of SMAD4, alternative factors may take over the gene regulatory functions of SMAD4 to drive EMT ( 46 ). In this vein, it has been shown that in a SMAD4-null context, SMAD2 and SMAD3 transduce TGFβ-driven cell migratory and invasive properties via the initiation of a SMAD4-independent “collective migration” transcriptional program ( 47 ). Dynamic assembly of cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss

Erasimus

Kolnik

Lacroix

et al. 2023

Cancer Research Communications

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The TGF-β signaling mediator SMAD4 is frequently mutated or deleted in colorectal and pancreatic cancers. SMAD4 acts as a tumor suppressor and its loss is associated with poorer patient outcomes. The purpose of this study was to find synthetic lethal interactions with SMAD4 deficiency in order to find novel therapeutic strategies for the treatment of patients with SMAD4-deficient colorectal or pancreatic cancers. Using pooled lentiviral sgRNA libraries, we conducted genome-wide loss-of-function screens in Cas9-expressing colorectal and pancreatic cancer cells harboring altered or wild-type SMAD4. The small GTPase protein RAB10 was identified and validated as a susceptibility gene in SMAD4-altered colorectal and pancreatic cancer cells. Rescue assays showed that RAB10 re-introduction reversed the anti-proliferative effects of RAB10 KO in SMAD4 negative cell lines. Further investigation is necessary to shed light on the mechanism by which RAB10 inhibition decreases cell proliferation of SMAD4-negative cells.

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SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4

Cited by 25 publications

References 73 publications

Experimental Studies on the Effects of Glycitinregulated TGF-β Signaling Pathway on the Proliferation, Osteogenic, and Lipogenic Differentiation of BMSCs

Experimental Studies on the Effects of Glycitinregulated TGF-β Signaling Pathway on the Proliferation, Osteogenic, and Lipogenic Differentiation of BMSCs

CDCA5 promoted cell invasion and migration by activating TGF-β1 pathway in human ovarian cancer cells

Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss

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