scholarly journals IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Minami Ando ◽  
Shigeyuki Magi ◽  
Masahide Seki ◽  
Yutaka Suzuki ◽  
Takeya Kasukawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Negative Feedback ◽  
Target Genes ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Transcriptional Induction ◽  
Feedback Regulator ◽  
Mcf 7 ◽  
Transcription Cycle

AbstractInflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα’s role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.

scholarly journals Alterations of Growth and Focal Adhesion Molecules in Human Breast Cancer Cells Exposed to the Random Positioning Machine

2021 ◽  
Vol 9 ◽  
Author(s):  
Jayashree Sahana ◽  
Thomas J. Corydon ◽  
Markus Wehland ◽  
Marcus Krüger ◽  
Sascha Kopp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Target Genes ◽  
Interaction Analysis ◽  
Expression Patterns ◽  
Focal Adhesions ◽  
Multicellular Spheroids ◽  
Down Regulation ◽  
Random Positioning Machine ◽  
Mcf 7

In this study, we evaluated changes in focal adhesions (FAs) in two types of breast cancer cell (BCC) lines (differentiated MCF-7 and the triple-negative MDA-MB-231 cell line) exposed to simulated microgravity (s-μg) created by a random positioning machine (RPM) for 24 h. After exposure, the BCC changed their growth behavior and exhibited two phenotypes in RPM samples: one portion of the cells grew as a normal two-dimensional monolayer [adherent (AD) BCC], while the other portion formed three-dimensional (3D) multicellular spheroids (MCS). After 1 h and 30 min (MDA-MB-231) and 1 h 40 min (MCF-7), the MCS adhered completely to the slide flask bottom. After 2 h, MDA-MB-231 MCS cells started to migrate, and after 6 h, a large number of the cells had left the MCS and continued to grow in a scattered pattern, whereas MCF-7 cells were growing as a confluent monolayer after 6 h and 24 h. We investigated the genes associated with the cytoskeleton, the extracellular matrix and FAs. ACTB, TUBB, FN1, FAK1, and PXN gene expression patterns were not significantly changed in MDA-MB-231 cells, but we observed a down-regulation of LAMA3, ITGB1 mRNAs in AD cells and of ITGB1, TLN1 and VCL mRNAs in MDA-MB-231 MCS. RPM-exposed MCF-7 cells revealed a down-regulation in the gene expression of FAK1, PXN, TLN1, VCL and CDH1 in AD cells and PXN, TLN and CDH1 in MCS. An interaction analysis of the examined genes involved in 3D growth and adhesion indicated a central role of fibronectin, vinculin, and E-cadherin. Live cell imaging of eGFP-vinculin in MCF-7 cells confirmed these findings. β-catenin-transfected MCF-7 cells revealed a nuclear expression in 1g and RPM-AD cells. The target genes BCL9, MYC and JUN of the Wnt/β-catenin signaling pathway were differentially expressed in RPM-exposed MCF-7 cells. These findings suggest that vinculin and β-catenin are key mediators of BCC to form MCS during 24 h of RPM-exposure.

scholarly journals DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Justine S. Habibian ◽  
Mitra Jefic ◽  
Rushita A. Bagchi ◽  
Robert H. Lane ◽  
Robert A. McKnight ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Feedback Regulator

scholarly journals Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10468
Author(s):  
Kai Zhang ◽  
Kuikui Jiang ◽  
Ruoxi Hong ◽  
Fei Xu ◽  
Wen Xia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Target Genes ◽  
Expression Profiles ◽  
Tamoxifen Resistance ◽  
Gene Expression Profiles ◽  
Gene Expression Omnibus ◽  
Ppi Network ◽  
Hub Genes ◽  
Mcf 7

Background Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis. Methods Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein–protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay. Results We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes—ACLY, HSPD1, PFAS, GART, TXN, HSPH1, HSPE1, IRAS, TRAP1, and ATIC—might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes (TXN, HSPD1, HSPH1 and ATIC) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance (P = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance. Conclusion This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.

IκBε provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression

2006 ◽  
Vol 203 (6) ◽  
pp. i18-i18
Author(s):  
Jeffrey D. Kearns ◽  
Soumen Basak ◽  
Shannon L. Werner ◽  
Christine S. Huang ◽  
Alexander Hoffmann
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Signaling Dynamics

scholarly journals Stable Inhibition of Specific Estrogen Receptor α (ERα) Phosphorylation Confers Increased Growth, Migration/Invasion, and Disruption of Estradiol Signaling in MCF-7 Breast Cancer Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4144-4159 ◽  
Author(s):  
B. P. Huderson ◽  
T. T. Duplessis ◽  
C. C. Williams ◽  
H. C. Seger ◽  
C. G. Marsden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Expression Patterns ◽  
Estrogen Receptor Α ◽  
Regulated Gene Expression ◽  
Mcf 7

Elevated phosphorylation of estrogen receptor α (ERα) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ERα signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ERα signaling, resulting in aggressive ERα-independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ERα-specific short hairpin RNA that reduced endogenous ERα. The resulting cell line was stably transfected with wild-type ERα (ER-AB cells), or ERα containing serine to alanine mutation at S118 or S167 (S118A cells and S167A cells, respectively). These stable cell lines expressed approximately equivalent ERα compared with parental MCF-7 cells and were evaluated for growth, morphology, migration/invasion, and ERα-regulated gene expression. S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro. Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size, and both S118A and S167A cells exhibited less cellular complexity. S118A and S167A cells expressed pancytokeratin and membrane localization of β-catenin and did not express vimentin, indicating retention of epithelial lineage markers. Expression of ERα-target genes and other genes regulated by ERα signaling or involved in breast cancer were markedly altered in both S118A and S167A cells. In summary, attenuated phosphorylation of ERα at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells, resulting in increased growth, migration/invasion, compromised expression of ERα target genes, and markedly altered gene expression patterns.

scholarly journals DAPK-ZIPK-L13a Axis Constitutes a Negative-Feedback Module Regulating Inflammatory Gene Expression

2008 ◽  
Vol 32 (3) ◽  
pp. 371-382 ◽  
Author(s):  
Rupak Mukhopadhyay ◽  
Partho Sarothi Ray ◽  
Abul Arif ◽  
Anna K. Brady ◽  
Michael Kinter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Feedback Module
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