Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion

2012 ◽  
Vol 447 (1) ◽  
pp. 81-91 ◽  
Author(s):  
Sarwat Naz ◽  
Prathibha Ranganathan ◽  
Priyanka Bodapati ◽  
Arun H. Shastry ◽  
Laxmi N. Mishra ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Transforming Growth Factor ◽  
P53 Protein ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Potential Biomarker ◽  
Tgf Β1

S100A2, an EF hand calcium-binding protein, is a potential biomarker in several cancers and is also a TGF-β (transforming growth factor-β)-regulated gene in melanoma and lung cancer cells. However, the mechanism of S100A2 regulation by TGF-β and its significance in cancer progression remains largely unknown. In the present study we report the mechanism of S100A2 regulation by TGF-β and its possible role in TGF-β-mediated tumour promotion. Characterization of the S100A2 promoter revealed an AP-1 (activator protein-1) element at positions −1161 to −1151 as being the most critical factor for the TGF-β1 response. Chromatin immunoprecipitation and electrophoretic mobility-shift assays confirmed the functional binding of the AP-1 complex, predominantly JunB, to the S100A2 promoter in response to TGF-β1 in HaCaT keratinocytes. JunB overexpression markedly stimulated the S100A2 promoter which was blocked by the dominant–negative JunB and MEK1 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1] inhibitor, PD98059. Intriguingly, despite the presence of a putative SMAD-binding element, S100A2 regulation by TGF-β1 was found to be SMAD3 independent. Interestingly, p53 protein and TGF-β1 show synergistic regulation of the S100A2 promoter. Finally, knockdown of S100A2 expression compromised TGF-β1-induced cell migration and invasion of Hep3B cells. Together our findings highlight an important link between the TGF-β1-induced MAPK and p53 signalling pathways in the regulation of S100A2 expression and pro-tumorigenic actions.

scholarly journals Rapid Up-Regulation of α4 Integrin-mediated Leukocyte Adhesion by Transforming Growth Factor-β1

2003 ◽  
Vol 14 (1) ◽  
pp. 54-66 ◽  
Author(s):  
Rubén A. Bartolomé ◽  
Francisco Sanz-Rodrı́guez ◽  
Mar M. Robledo ◽  
Andrés Hidalgo ◽  
Joaquin Teixidó
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Peripheral Blood ◽  
Transforming Growth Factor Β1 ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Tgf Β1

The α4 integrins (α4β1 and α4β7) are cell surface heterodimers expressed mostly on leukocytes that mediate cell-cell and cell-extracellular matrix adhesion. A characteristic feature of α4 integrins is that their adhesive activity can be subjected to rapid modulation during the process of cell migration. Herein, we show that transforming growth factor-β1 (TGF-β1) rapidly (0.5–5 min) and transiently up-regulated α4 integrin-dependent adhesion of different human leukocyte cell lines and human peripheral blood lymphocytes (PBLs) to their ligands vascular cell adhesion molecule-1 (VCAM-1) and connecting segment-1/fibronectin. In addition, TGF-β1 enhanced the α4 integrin-mediated adhesion of PBLs to tumor necrosis factor-α–treated human umbilical vein endothelial cells, indicating the stimulation of α4β1/VCAM-1 interaction. Although TGF-β1 rapidly activated the small GTPase RhoA and the p38 mitogen-activated protein kinase, enhanced adhesion did not require activation of both signaling molecules. Instead, polymerization of actin cytoskeleton triggered by TGF-β1 was necessary for α4 integrin-dependent up-regulated adhesion, and elevation of intracellular cAMP opposed this up-regulation. Moreover, TGF-β1 further increased cell adhesion mediated by α4 integrins in response to the chemokine stromal cell-derived factor-1α. These data suggest that TGF-β1 can potentially contribute to cell migration by dynamically regulating cell adhesion mediated by α4 integrins.

scholarly journals Activation of Slit2/Robo1 Signaling Promotes Tumor Metastasis in Colorectal Carcinoma through Activation of the TGF-β/Smads Pathway

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 635 ◽  
Author(s):  
Yuying Yao ◽  
Zijun Zhou ◽  
Liuyou Li ◽  
Junchen Li ◽  
Lixun Huang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Metastasis ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Transforming Growth Factor Β1 ◽  
Migration And Invasion ◽  
Tumor Cell Migration ◽  
Pathological Stages ◽  
Tgf Β1

Slit2 (slit guidance ligand 2), a ligand of the Roundabout1 (Robo1) transmembrane receptor, is often overexpressed in colorectal carcinomas (CRCs). In this study, we performed data mining in the Metabolic gEne RApid Visualizer (MERAV) database and found that Slit2 and TGF-β1 (Transforming growth factor-β1) are highly expressed in carcinomas relative to those in tumor-free tissues from healthy volunteers or wild type mice. Furthermore, expression of Slit2 and TGF-β1 in CRCs increases with pathological stages. Serum levels of Slit2 in patients with CRC and in ApcMin/+ mice with spontaneous intestinal adenoma were significantly increased compared with those in healthy controls. Specific blockage of Slit2 binding to Robo1 inactivated TGF-β/Smads signaling and inhibited tumor cell migration and metastasis, which can be partially restored by treatment with TGF-β1. However, specific inhibition of TGF-β1/Smads signaling reduced CRC tumor cell migration and invasion without affecting cell proliferation. This study suggests that activation of Slit2/Robo1 signaling in CRC induces tumor metastasis partially through activation of the TGF-β/Smads pathway.

scholarly journals O-GlcNAcylation of MORC2 at threonine 556 by OGT couples TGF-β signaling to breast cancer progression

2022 ◽  
Author(s):  
Ying-Ying Liu ◽  
Hong-Yi Liu ◽  
Tian-Jian Yu ◽  
Qin Lu ◽  
Fang-Lin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Growth Factor ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Tgf Β1

AbstractMORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-β1 (TGF-β1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-β1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-β1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.

scholarly journals RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1569 ◽  
Author(s):  
Rabea Zinn ◽  
Hannah Otterbein ◽  
Hendrik Lehnert ◽  
Hendrik Ungefroren
Keyword(s):  
Gene Expression ◽  
Cell Migration ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Migratory Activity ◽  
Tgf Β1

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

Transforming growth factor-β1 regulates macrophage migration via RhoA

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1821-1829 ◽  
Author(s):  
Jun-Sub Kim ◽  
Jae-Gyu Kim ◽  
Mi-Young Moon ◽  
Chan-Young Jeon ◽  
Ha-Young Won ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rho Gtpase ◽  
Initial Period ◽  
Transforming Growth Factor Β1 ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Protein Levels ◽  
Tgf Β1

Abstract Brief treatment with transforming growth factor (TGF)–β1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-β1 was markedly inhibited by 10 μg/mL Tat-C3 exoenzyme. TGF-β1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)–1α in the initial period, and these effects also were inhibited by 10 μg/mL Tat-C3 and a dominant-negative (DN)–RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1α and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-β1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1α and MCP-1 mediated by RhoA in response to TGF-β1. TGF-β1 activated RhoA in the initial period, and thereafter inactivated them, suggesting that the inactivation of RhoA may be the cause of the reduced cell migration in response to TGF-β1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-β1. First, TGF-β1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA. Second, wild-type p190 Rho GTPase activating protein (p190RhoGAP) reduced and DN-p190RhoGAP reversed the reduction of cell migration induced by TGF-β, suggesting that it inactivated RhoA via p190 Rho GAP.

scholarly journals Redox Regulation of NOX Isoforms on FAK(Y397)/SRC(Y416) Phosphorylation Driven Epithelial-to-Mesenchymal Transition in Malignant Cervical Epithelial Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1555
Author(s):  
Young Mee Kim ◽  
Karthika Muthuramalingam ◽  
Moonjae Cho
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Cellular Localization ◽  
Redox Regulation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
Src Pathway

Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in tumorigenesis and organ fibrosis. Growth factors such as epidermal growth factor and fibroblast growth factor in addition to cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of cancer progression such as invasion, metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms—NOX2 and NOX4—that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the focal adhesion kinase (FAK)/SRC pathway in HeLa, human cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of cytokine mediated EMT and its associated processes via tyrosine phosphorylation of the FAK/SRC pathway.

scholarly journals Ailanthoidol, a Neolignan, Suppresses TGF-β1-Induced HepG2 Hepatoblastoma Cell Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1110
Author(s):  
Tsui-Hwa Tseng ◽  
Huei-Jane Lee ◽  
Yean-Jang Lee ◽  
Ko-Chao Lee ◽  
Chien-Heng Shen ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Mouse Skin ◽  
Transforming Growth Factor Β1 ◽  
Mitogen Activated Protein Kinase ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Induced Expression ◽  
Tgf Β1

Ailanthoidol (ATD), a neolignan, possessed an antitumor promotion effect in the mouse skin model in our previous investigation. However, other antitumor properties remain to be elucidated. Liver cancer is a major cause of death in the world, and its prognosis and survival rate are poor. Therefore, the prevention and therapy of liver cancer have received much attention. TGF (transforming growth factor)-β1, a cytokine, plays a critical role in the progression of liver cancer. This study determined the inhibitory effects of ATD on the migration and invasion induced by TGF-β1 in HepG2 hepatoblastoma cells. Furthermore, ATD reduced the TGF-β1-promoted colony number of HepG2 hepatoblastoma cells. In addition to reversing TGF-β1-induced cell scattering, ATD suppressed TGF-β1-induced expression of integrin α3, vimentin, N-cadherin, and matrix metalloproteinase 2 (MMP2). Finally, this study found that ATD significantly inhibited TGF-β1-promoted phosphorylation of p-38 mitogen-activated protein kinase (MAPK) and Smad 2. Furthermore, the administration of SB203580 (p38MAPK inhibitor) suppressed TGF-β1-induced expression of integrin α3, N-cadherin, and MMP2. These results demonstrate a novel mechanism of ATD against progression of liver cancer.

scholarly journals Transforming Growth Factor-β1 (TGF-β)–induced Apoptosis of Prostate Cancer Cells Involves Smad7-dependent Activation of p38 by TGF-β-activated Kinase 1 and Mitogen-activated Protein Kinase Kinase 3

2003 ◽  
Vol 14 (2) ◽  
pp. 529-544 ◽  
Author(s):  
Sofia Edlund ◽  
Shizhong Bu ◽  
Norbert Schuster ◽  
Pontus Aspenström ◽  
Rainer Heuchel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Tgf Β1 ◽  
Protein Kinase Kinase

The inhibitory Smad7, a direct target gene for transforming growth factor-β (TGF-β), mediates TGF-β1–induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-β1 or Smad7 overexpression is caused by a specific activation of the p38 mitogen-activated protein kinase pathway in a TGF-β–activated kinase 1 (TAK1)- and mitogen-activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], prevented TGF-β1–induced apoptosis. The expression of Smad7 was required for TGF-β–induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent manner. Ectopic expression of wild-type TAK1 promoted TGF-β1–induced phosphorylation of p38 and apoptosis, whereas dominant negative TAK1 reduced TGF-β1–induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3, and p38 were coimmunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38.

Transforming Growth Factor Beta 1 Affects Gastric Cancer Cell Proliferation, Migration, and Invasion by Regulating Phosphatase and Tensin Homolog

2021 ◽  
Vol 11 (4) ◽  
pp. 731-735
Author(s):  
Yuchen Wang ◽  
Zhimin Huang
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cancer Cell ◽  
Transforming Growth Factor Beta ◽  
Gastric Cancer Cell ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Control Group ◽  
Tgf Β1

Gastric cancer (GC) is a common tumor with high incidence and poor prognosis. So far, the pathogenesis of GC has not been fully elucidated, which has brought great difficulty to the treatment. TGF-β regulates cell growth and differentiation. As a key member, TGF-β1 is abnormally expressed in various tumors, but its role on GC and related mechanisms have not been elucidated. Gastric cancer and adjacent tissues were collected to measure TGF-β1 level by real-time PCR. SGC-7901 cell was assigned into control group, mock group, and TGF-β1 siRNA group followed by analysis of TGF-β1 level by ELISA, cell proliferation by MTT assay, apoptosis by flow cytometry, cell migration by cell scratch test, cell invasion by Transwell chamber assay, and Bcl-2, Bax, and PTEN level by Western blot. TGF-β1 was significantly upregulated in GC tissues (P <0.05) and increased with TNM stage dependence. TGF-β1 siRNA transfection significantly decreased TGF-β1 mRNA level and secretion, inhibited cell proliferation, increased apoptosis rate, and attenuated cell migration and invasion along with downregulated Bcl-2 and elevated Bax and PTEN expression (P <0.05). Downregulation of TGF-β1 can promote gastric cancer cell apoptosis, inhibit proliferation, migration, and invasion by regulating PTEN.

p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration

2002 ◽  
Vol 115 (15) ◽  
pp. 3193-3206 ◽  
Author(s):  
Andrei V. Bakin ◽  
Cammie Rinehart ◽  
Anne K. Tomlinson ◽  
Carlos L. Arteaga
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Mitogen Activated Protein ◽  
P38mapk Pathway

Transforming growth factor β (TGFβ) contributes to tumor progression by inducing an epithelial to mesenchymal transdifferentiation(EMT) and cell migration. We found that TGFβ-induced EMT was blocked by inhibiting activation of p38 mitogen-activated protein kinase (MAPK) with H-7,a protein kinase C inhibitor, and with SB202190, a direct inhibitor of p38MAPK. Inhibition of the p38MAPK pathway affected TGFβ-mediated phosphorylation of ATF2, but did not inhibit phosphorylation of Smad2. SB202190 impaired TGFβ-mediated changes in cell shape and reorganization of the actin cytoskeleton. Forced expression of dominant-negative (DN) MAPK kinase 3 (MKK3) inhibited TGFβ-mediated activation of p38MAPK and EMT. Expression of DN-p38α impaired TGFβ-induced EMT. Inhibition of p38MAPK blocked TGFβ-induced migration of non-tumor and tumor mammary epithelial cells. TGFβ induced activation of the p38MAPK pathway within 15 minutes. Expression of TGFβ type II (TβRII) and type I(TβRI/Alk5) kinase-inactive receptors blocked EMT and activation of p38MAPK, whereas expression of constitutively active Alk5-T204D resulted in EMT and phosphorylation of MKK3/6 and p38MAPK. Finally, dominant-negative Rac1N17 blocked TGFβ-induced activation of the p38MAPK pathway and EMT,suggesting that Rac1 mediates activation of the p38MAPK pathway. These studies suggest that the p38MAPK pathway is required for TGFβ-mediated EMT and cell migration.

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