The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela−/−mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration–associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505–dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.

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Sprouty3 and Sprouty4, Two Members of a Family Known to Inhibit FGF-Mediated Signaling, Exert Opposing Roles on Proliferation and Migration of Glioblastoma-Derived Cells

Cells ◽

10.3390/cells8080808 ◽

2019 ◽

Vol 8 (8) ◽

pp. 808 ◽

Cited By ~ 7

Author(s):

Burcu Emine Celik-Selvi ◽

Astrid Stütz ◽

Christoph-Erik Mayer ◽

Jihen Salhi ◽

Gerald Siegwart ◽

...

Keyword(s):

Cell Lines ◽

Receptor Tyrosine Kinase ◽

Brain Cancer ◽

Mapk Pathway ◽

Ectopic Expression ◽

Negative Regulator ◽

Oncogenic Potential ◽

And Migration ◽

Proliferation And Migration

Dysregulation of receptor tyrosine kinase-induced pathways is a critical step driving the oncogenic potential of brain cancer. In this study, we investigated the role of two members of the Sprouty (Spry) family in brain cancer-derived cell lines. Using immunoblot analyses we found essential differences in the pattern of endogenous Spry3 and Spry4 expression. While Spry4 expression was mitogen-dependent and repressed in a number of cells from higher malignant brain cancers, Spry3 levels neither fluctuated in response to serum withdrawal nor were repressed in glioblastoma (GBM)-derived cell lines. In accordance to the well-known inhibitory role of Spry proteins in fibroblast growth factor (FGF)-mediated signaling, both Spry proteins were able to interfere with FGF-induced activation of the MAPK pathway although to a different extent. In response to serum solely, Spry4 exerts its role as a negative regulator of MAPK activation. Ectopic expression of Spry4 inhibited proliferation and migration of GBM-originated cells, positioning it as a tumor suppressor in brain cancer. In contrast, elevated Spry3 levels accelerated both proliferation and migration of these cell lines, while repression of Spry3 levels using shRNA caused a significant diminished growth and migration velocity rate of a GBM-derived cell line. This argues for a tumor-promoting function of Spry3 in GBMs. Based on these data we conclude that Spry3 and Spry4 fulfill different if not opposing roles within the cancerogenesis of brain malignancies.

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Ion channels and transporters in the development of drug resistance in cancer cells

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0109 ◽

2014 ◽

Vol 369 (1638) ◽

pp. 20130109 ◽

Cited By ~ 62

Author(s):

Else K. Hoffmann ◽

Ian H. Lambert

Keyword(s):

Drug Resistance ◽

Ion Channels ◽

Drug Uptake ◽

Multi Drug Resistance ◽

Drug Efflux ◽

Ion Transporters ◽

Drug Induced ◽

And Migration ◽

Induced Apoptosis ◽

Proliferation And Migration

Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion transporters is the main focus of this paper and we demonstrate how pro-apoptotic ion channels are downregulated, while anti-apoptotic ion transporters are upregulated in MDR. We also discuss whether upregulation of ion transport proteins that are important for proliferation contribute to MDR. Finally, we discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis.

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SnoN facilitates ALK1–Smad1/5 signaling during embryonic angiogenesis

The Journal of Cell Biology ◽

10.1083/jcb.201208113 ◽

2013 ◽

Vol 202 (6) ◽

pp. 937-950 ◽

Cited By ~ 10

Author(s):

Qingwei Zhu ◽

Yong Hwan Kim ◽

Douglas Wang ◽

S. Paul Oh ◽

Kunxin Luo

Keyword(s):

Endothelial Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Endothelial Cell Proliferation ◽

Type I ◽

Positive Role ◽

And Migration ◽

Proliferation And Migration

In endothelial cells, two type I receptors of the transforming growth factor β (TGF-β) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-β. Whereas TGF-β binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-β also bind to ALK1, resulting in the activation of Smad1/5. SnoN is a negative regulator of ALK5 signaling through the binding and repression of Smad2/3. Here we uncover a positive role of SnoN in enhancing Smad1/5 activation in endothelial cells to promote angiogenesis. Upon ligand binding, SnoN directly bound to ALK1 on the plasma membrane and facilitated the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of this SnoN–Smad interaction impaired Smad1/5 activation and up-regulated Smad2/3 activity. This resulted in defective angiogenesis and arteriovenous malformations, leading to embryonic lethality at E12.5. Thus, SnoN is essential for TGF-β/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.

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Long intergenic non-coding RNA 1939 inhibits proliferation and migration of human renal cell carcinoma (RCC) cells by down-regulation of miR-154

10.21203/rs.2.10547/v1 ◽

2019 ◽

Author(s):

Rongyuan Zhang ◽

Yuhua Huang ◽

Baocai Xu ◽

Chuan Lv ◽

Jianquan Hou ◽

...

Keyword(s):

Flow Cytometric Analysis ◽

Cell Counting ◽

Regulation Mechanism ◽

Human Renal Cell Carcinoma ◽

Flow Cytometric ◽

Non Coding Rna ◽

And Migration ◽

Induced Apoptosis ◽

Proliferation And Migration

Abstract Background: Renal carcinoma (RCC) is widely accepted as a malignant tumor of urinary system. Long intergenic non-coding RNA 1939 (LINC01939) is a novel lncRNA which was found to be down-regulated in RCC. Thus, we set out to explore the effect and regulation mechanism of LINC01939 in RCC. Methods: LINC01939 and miR-154 in RCC tissues and cell lines were detected using qRT-PCR assay. Cell counting kit-8 (CCK-8) assays was exploited to examine cell viability. Flow cytometric analysis was conducted to examine apoptosis. Cell mobility was valued through wound healing assays. Western blotting was applied for examination of proteins related to proliferation, apoptosis, migration and Wnt/β-catenin/Notch. Results: LINC01939 was down-regulated in RCC tissues. LINC01939 overexpression impeded proliferation and migration, and induced apoptosis. Further study found that the overexpression of LINC01939 strongly suppressed miR-154 expression. Then, the inhibiting effect of overexpressed LINC01939 on proliferation and mobility and the promoting role of LINC01939 in apoptosis were abolished by the combination of miR-154 mimic. Finally, we found that the overexpressed LINC01939 inactivated Wnt/β-catenin and Notch through suppressing miR-154. Conclusion: The up-regulation of LINC01939 inhibited proliferation and migration of RCC cells by down-regulating miR-154.

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Role of microenvironment on proliferation and migration of an SDHB silenced murine Pheochromocytoma cell line

Endocrine Abstracts ◽

10.1530/endoabs.49.ep93 ◽

2017 ◽

Author(s):

Serena Martinelli ◽

Vanessa D'Antongiovanni ◽

Susan Richter ◽

Letizia Canu ◽

Tonino Ercolino ◽

...

Keyword(s):

Cell Line ◽

Pheochromocytoma Cell ◽

And Migration ◽

Proliferation And Migration

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Exosomal miR-214-5p Released from Glioblastoma Cells Modulates Inflammatory Response of Microglia after Lipopolysaccharide Stimulation through Targeting CXCR5

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666181105112009 ◽

2019 ◽

Vol 18 (1) ◽

pp. 78-87 ◽

Cited By ~ 7

Author(s):

Jian-kai Yang ◽

Hong-jiang Liu ◽

Yuanyu Wang ◽

Chen Li ◽

Ji-peng Yang ◽

...

Keyword(s):

Inflammatory Response ◽

Critical Role ◽

Luciferase Reporter ◽

Clinical Prognosis ◽

Direct Target ◽

And Migration ◽

High Level ◽

Cxcr5 Expression ◽

Proliferation And Migration

Background and Objective: Exosomes communicate inter-cellularly and miRNAs play critical roles in this scenario. MiR-214-5p was implicated in multiple tumors with diverse functions uncovered. However, whether miR-214-5p is mechanistically involved in glioblastoma, especially via exosomal pathway, is still elusive. Here we sought to comprehensively address the critical role of exosomal miR-214-5p in glioblastoma (GBM) microenvironment.Methods:The relative expression of miR-214-5p was determined by real-time PCR. Cell viability and migration were measured by MTT and transwell chamber assays, respectively. The secretory cytokines were measured with ELISA kits. The regulatory effect of miR-214-5p on CXCR5 expression was interrogated by luciferase reporter assay. Protein level was analyzed by Western blot.Results:We demonstrated that miR-214-5p was aberrantly overexpressed in GBM and associated with poorer clinical prognosis. High level of miR-214-5p significantly contributed to cell proliferation and migration. GBM-derived exosomal miR-214-5p promoted inflammatory response in primary microglia upon lipopolysaccharide challenge. We further identified CXCR5 as the direct target of miR-214- 5p in this setting.Conclusion:Overexpression of miR-214-5p in GBM modulated the inflammatory response in microglia via exosomal transfer.

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Retraction: RNA-sequencing identified miR-3681 as a negative regulator in the proliferation and migration of cervical cancer cells via the posttranscriptional suppression of HGFR

RSC Advances ◽

10.1039/d1ra90052h ◽

2021 ◽

Vol 11 (9) ◽

pp. 5230-5230

Author(s):

Laura Fisher

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Rna Sequencing ◽

Negative Regulator ◽

Cervical Cancer Cells ◽

And Migration ◽

Proliferation And Migration

Retraction of ‘RNA-sequencing identified miR-3681 as a negative regulator in the proliferation and migration of cervical cancer cells via the posttranscriptional suppression of HGFR’ by Fan Shi et al., RSC Adv., 2019, 9, 22376–22383, DOI: 10.1039/C9RA01785B.

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Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽

10.1182/blood.v96.13.4142 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4142-4151 ◽

Cited By ~ 108

Author(s):

Marcin Majka ◽

Anna Janowska-Wieczorek ◽

Janina Ratajczak ◽

M. Anna Kowalska ◽

Gaston Vilaire ◽

...

Keyword(s):

Protein Kinase ◽

Intracellular Signaling ◽

Phosphatidyl Inositol ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Proliferative Effect ◽

Normal Human ◽

And Migration ◽

Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

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RNA-sequencing identified miR-3681 as a negative regulator in the proliferation and migration of cervical cancer cells via the posttranscriptional suppression of HGFR

RSC Advances ◽

10.1039/c9ra01785b ◽

2019 ◽

Vol 9 (39) ◽

pp. 22376-22383 ◽

Cited By ~ 1

Author(s):

Fan Shi ◽

Yingbing Zhang ◽

Juan Wang ◽

Jin Su ◽

Zi Liu ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Rna Sequencing ◽

Negative Regulator ◽

Tumor Tissues ◽

Differentially Expressed Mirnas ◽

Cervical Cancer Cells ◽

And Migration ◽

Cancer Tissues ◽

Proliferation And Migration

In this study, RNA-sequencing was used to investigate the differentially expressed miRNAs between cervical cancer tissues and matched adjacent non-tumor tissues.

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The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

Mediators of Inflammation ◽

10.1155/2012/512926 ◽

2012 ◽

Vol 2012 ◽

pp. 1-18 ◽

Cited By ~ 115

Author(s):

Se Eun Byeon ◽

Young-Su Yi ◽

Jueun Oh ◽

Byong Chul Yoo ◽

Sungyoul Hong ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Src Kinase ◽

Multiple Roles ◽

Cellular Migration ◽

Pharmaceutical Drugs ◽

Tyrosine Protein Kinase

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

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