scholarly journals c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Nicolas Pallet ◽  
Eric Thervet ◽  
Dany Anglicheau
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Epithelial To Mesenchymal Transition ◽  
Primary Cultures ◽  
Independent Manner ◽  
Jnk Signaling ◽  
Mesenchymal Transition ◽  
Morphological Alterations ◽  
Phenotypic Changes

Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-β-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression.

scholarly journals ER Stress is Involved in Epithelial-To-Mesenchymal Transition of Alveolar Epithelial Cells Exposed to a Hypoxic Microenvironment

2019 ◽  
Vol 20 (6) ◽  
pp. 1299 ◽  
Author(s):  
Eva Delbrel ◽  
Yurdagül Uzunhan ◽  
Abdoulaye Soumare ◽  
Thomas Gille ◽  
Dominique Marchant ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Epithelial To Mesenchymal Transition ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Rat Lungs ◽  
Fibrotic Process

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease of unknown origin. Alveolar epithelial cells (AECs) play an important role in the fibrotic process as they undergo sustained endoplasmic reticulum (ER) stress, and may acquire a mesenchymal phenotype through epithelial-to-mesenchymal transition (EMT), two phenomena that could be induced by localized alveolar hypoxia. Here we investigated the potential links between hypoxia, ER stress and EMT in AECs. Methods: ER stress and EMT markers were assessed by immunohistochemistry, western blot and qPCR analysis, both in vivo in rat lungs exposed to normoxia or hypoxia (equivalent to 8% O2) for 48 h, and in vitro in primary rat AECs exposed to normoxia or hypoxia (1.5% O2) for 2–6 days. Results: Hypoxia induced expression of mesenchymal markers, pro-EMT transcription factors, and the activation of ER stress markers both in vivo in rat lungs, and in vitro in AECs. In vitro, pharmacological inhibition of ER stress by 4-PBA limited hypoxia-induced EMT. Calcium chelation or hypoxia-inducible factor (HIF) inhibition also prevented EMT induction under hypoxic condition. Conclusions: Hypoxia and intracellular calcium are both involved in EMT induction of AECs, mainly through the activation of ER stress and HIF signaling pathways.

Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells

2008 ◽  
Vol 295 (1) ◽  
pp. F82-F90 ◽  
Author(s):  
Min Li ◽  
Saravanan Balamuthusamy ◽  
Eric E. Simon ◽  
Vecihi Batuman
Keyword(s):  
Epithelial Cells ◽  
Proximal Tubule ◽  
Light Chain ◽  
Epithelial To Mesenchymal Transition ◽  
Human Kidney ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Mesenchymal Transition ◽  
Morphological Alterations

Using target-specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to κ-light chain for up to 24 h, light chain endocytosis was reduced in either megalin- or cubilin-silenced cells markedly but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near-complete inhibition of light chain endocytosis, as determined by measuring κ-light chain protein concentration in cell cytoplasm and by flow cytometry using FITC-labeled κ-light chain. In these cells, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells.

scholarly journals Altered Epithelial-mesenchymal Plasticity as a Result of Ovol2 Deletion Minimally Impacts the Self-renewal of Adult Mammary Basal Epithelial Cells

2022 ◽  
Author(s):  
Peng Sun ◽  
Yingying Han ◽  
Maksim Plikus ◽  
Xing Dai
Keyword(s):  
Epithelial Cells ◽  
Basal Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Basal Cells ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Transcriptional State ◽  
Specific Deletion ◽  
Basal Epithelial Cells

AbstractStem-cell containing mammary basal epithelial cells exist in a quasi-mesenchymal transcriptional state characterized by simultaneous expression of typical epithelial genes and typical mesenchymal genes. Whether robust maintenance of such a transcriptional state is required for adult basal stem cells to fuel self-renewal and regeneration remains unclear. In this work, we utilized SMA-CreER to direct efficient basal cell-specific deletion of Ovol2, which encodes a transcription factor that inhibits epithelial-to-mesenchymal transition (EMT), in adult mammary gland. We identified a basal cell-intrinsic role of Ovol2 in promoting epithelial, and suppressing mesenchymal, molecular traits. Interestingly, Ovol2-deficient basal cells display minimal perturbations in their ability to support tissue homeostasis, colony formation, and transplant outgrowth. These findings underscore the ability of adult mammary basal cells to tolerate molecular perturbations associated with altered epithelia-mesenchymal plasticity without drastically compromising their self-renewal potential.

scholarly journals ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation

2019 ◽  
Vol 116 (8) ◽  
pp. 2967-2976 ◽  
Author(s):  
Sejeong Shin ◽  
Gwen R. Buel ◽  
Michal J. Nagiec ◽  
Min-Joon Han ◽  
Philippe P. Roux ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Global Changes ◽  
Jnk Signaling ◽  
Mesenchymal Transition ◽  
Potential Mediator ◽  
Signaling Axis ◽  
Inducing Factors

ERK is a key coordinator of the epithelial-to-mesenchymal transition (EMT) in that a variety of EMT-inducing factors activate signaling pathways that converge on ERK to regulate EMT transcription programs. However, the mechanisms by which ERK controls the EMT program are not well understood. Through an analysis of the global changes of gene expression mediated by ERK2, we identified the transcription factor FoxO1 as a potential mediator of ERK2-induced EMT, and thus we investigated the mechanism by which ERK2 regulates FoxO1. Additionally, our analysis revealed that ERK2 induced the expression of Dock10, a Rac1/Cdc42 GEF, during EMT. We demonstrate that the activation of the Rac1/JNK signaling axis downstream of Dock10 leads to an increase in FoxO1 expression and EMT. Taken together, our study uncovers mechanisms by which epithelial cells acquire less proliferative but more migratory mesenchymal properties and reveals potential therapeutic targets for cancers evolving into a metastatic disease state.

scholarly journals Role of E2Fs and mitotic regulators controlled by E2Fs in the epithelial to mesenchymal transition

2019 ◽  
Vol 244 (16) ◽  
pp. 1419-1429
Author(s):  
Shirley Jusino ◽  
Harold I Saavedra
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Centrosome Amplification ◽  
Mesenchymal Transition

The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets. Impact statement The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.

scholarly journals TPM3.1 association with actin stress fibers is required for lens epithelial to mesenchymal transition

2019 ◽  
Author(s):  
Justin Parreno ◽  
Michael B. Amadeo ◽  
Elizabeth H. Kwon ◽  
Velia M. Fowler
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Stress Fiber ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Lens Epithelial Cells ◽  
Mesenchymal Transition ◽  
Stress Fiber Formation ◽  
Actin Stress Fibers

AbstractPurposeEpithelial to mesenchymal transition (EMT) is a cause of anterior and posterior subcapsular cataracts. Central to EMT is the formation of actin stress fibers. Targeting specific, stress fiber associated tropomyosin in epithelial cells may be a means to prevent stress fiber formation and repress lens EMT.MethodsWe identified Tpm isoforms in mouse immortalized lens epithelial cells and isolated whole lenses by semi-quantitative PCR followed Sanger sequencing. We focused on the role of one particular tropomyosin isoform, Tpm3.1, in EMT. To stimulate EMT, we cultured cells or native lenses in TGFβ2. To test the function of Tpm3.1, we exposed cells or whole lenses to a Tpm3.1-specific chemical inhibitor, TR100, as well as investigated lenses from Tpm3.1 knockout mice. We examined stress fiber formation by confocal microscopy and assessed EMT progression by αsma mRNA (qPCR) and protein (WES immunoassay) analysis.ResultsLens epithelial cells express eight tropomyosin isoforms. Cell culture studies showed that TGFβ2 treatment results in an upregulation of Tpm3.1, which associates with actin in stress fibers. TR100 prevents stress fiber formation and reduces αsma in TGFβ2 treated cells. We confirmed the role of Tpm3.1 in lens epithelial cells in the native lens ex vivo. Culture of whole lenses in the presence of TGFβ2 results in stress fiber formation at the basal regions of epithelial cells. Knockout of Tpm3.1 or treatment of lenses with TR100 prevents basal stress fiber formation and reduces epithelial αsma levels.ConclusionTargeting specific stress fiber associated tropomyosin isoform, Tpm3.1, is a means to represses lens EMT.

Sign in / Sign up

Export Citation Format

Share Document