scholarly journals Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

2018 ◽  
Author(s):  
John S Poulton ◽  
Daniel J McKay ◽  
Mark Peifer
Keyword(s):  
Oxidative Stress ◽  
Cellular Response ◽  
Target Genes ◽  
Cell Damage ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Spindle Assembly ◽  
Redox Balance ◽  
Mitotic Division

AbstractCentrosomes play a critical role in mitotic spindle assembly through their role in microtubule nucleation and bipolar spindle assembly. Loss of centrosomes can impair the ability of some cells to properly conduct mitotic division, leading to chromosomal instability, cell stress, and aneuploidy. Multiple aspects of the cellular response to mitotic error associated with centrosome loss appears to involve activation of JNK signaling. To further characterize the transcriptional effects of centrosome loss, we compared gene expression profiles of wildtype and acentrosomal cells from Drosophila wing imaginal discs. We found elevation of expression of JNK target genes, which we verified at the protein level. Consistent with this, the upregulated gene set showed significant enrichment for the AP1 consensus DNA binding sequence. We also found significant elevation in expression of genes regulating redox balance. Based on those findings, we examined oxidative stress after centrosome loss, revealing that acentrosomal wing cells have significant increases in reactive oxygen species (ROS). We then performed a candidate genetic screen and found that one of the genes upregulated in acentrosomal cells, G6PD, plays an important role in buffering acentrosomal cells against increased ROS and helps protect those cells from cell death. Our data and other recent studies have revealed a complex network of signaling pathways, transcriptional programs, and cellular processes that epithelial cells use to respond to stressors like mitotic errors to help limit cell damage and maintain normal tissue development.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals The Erythroid Phenotype of EKLF-Null Mice: Defects in Hemoglobin Metabolism and Membrane Stability

2005 ◽  
Vol 25 (12) ◽  
pp. 5205-5214 ◽  
Author(s):  
Roy Drissen ◽  
Marieke von Lindern ◽  
Andrea Kolbus ◽  
Siska Driegen ◽  
Peter Steinlein ◽  
...  
Keyword(s):  
Blood Cells ◽  
Target Genes ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Erythroid Differentiation ◽  
Membrane Stability ◽  
Erythroid Progenitors ◽  
Hemoglobin Metabolism

ABSTRACT Development of red blood cells requires the correct regulation of cellular processes including changes in cell morphology, globin expression and heme synthesis. Transcription factors such as erythroid Krüppel-like factor EKLF (Klf1) play a critical role in erythropoiesis. Mice lacking EKLF die around embryonic day 14 because of defective definitive erythropoiesis, partly caused by a deficit in β-globin expression. To identify additional target genes, we analyzed the phenotype and gene expression profiles of wild-type and EKLF null primary erythroid progenitors that were differentiated synchronously in vitro. We show that EKLF is dispensable for expansion of erythroid progenitors, but required for the last steps of erythroid differentiation. We identify EKLF-dependent genes involved in hemoglobin metabolism and membrane stability. Strikingly, expression of these genes is also EKLF-dependent in primitive, yolk sac-derived, blood cells. Consistent with lack of upregulation of these genes we find previously undetected morphological abnormalities in EKLF-null primitive cells. Our data provide an explanation for the hitherto unexplained severity of the EKLF null phenotype in erythropoiesis.

scholarly journals NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

2019 ◽  
Author(s):  
Ayse Z Sahan ◽  
Tatiana Venkova ◽  
Ibrahim M. Sayed ◽  
Ellen J Beswick ◽  
Victor E. Reyes ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Oxidative Dna Damage ◽  
Cell Damage ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Gastric Epithelial Cells ◽  
Down Regulation ◽  
H Pylori

AbstractThe accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; this response was more pronounced in Neil2 knockout (KO) mouse cells compared to wild type (WT) cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Interestingly, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. H. pylori-infected Neil2 KO mice showed higher inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of repair genes in gastric specimens showed the reduction of Neil2 level is linked to the GC progression. Taken together, our data suggest that down-regulation of NEIL2 is a plausible mechanism by which H. pylori infection derails DNA damage repair, amplifies the inflammatory response and initiates GCs.

Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Toshihiro Ichiki
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Prolyl Hydroxylase ◽  
Ang Ii ◽  
Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

The characteristics of mesenteric adipose tissue attached to different intestinal segments and their roles in immune regulation

2022 ◽  
Author(s):  
Haowei Zhang ◽  
Yujin Ding ◽  
Qin Zeng ◽  
Dandan Wang ◽  
Ganglei Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Immune Regulation ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Rna Seq ◽  
Mesenteric Adipose Tissue ◽  
Cell Components ◽  
Subsequent Effect

Background: Mesenteric adipose tissue (MAT) plays a critical role in the intestinal physiological ecosystems. Small and large intestines have evidently intrinsic and distinct characteristics. However, whether there exist any mesenteric differences adjacent to the small and large intestines (SMAT and LMAT) has not been properly characterized. We studied the important facets of these differences, such as morphology, gene expression, cell components and immune regulation of MATs, to characterize the mesenteric differences. Methods: The SMAT and LMAT of mice were utilized for comparison of tissue morphology. Paired mesenteric samples were analyzed by RNA-seq to clarify gene expression profiles. MAT partial excision models were constructed to illustrate the immune regulation roles of MATs, and 16S-seq was applied to detect the subsequent effect on microbiota. Results: Our data show that different segments of mesenteries have different morphological structures. SMAT not only has smaller adipocytes but also contains more fat-associated lymphoid clusters than LMAT. The gene expression profile is also discrepant between these two MATs in mice. B-cell markers were abundantly expressed in SMAT, while development-related genes were highly expressed in LMAT. Adipose-derived stem cells of LMAT exhibited higher adipogenic potential and lower proliferation rates than those of SMAT. In addition, SMAT and LMAT play different roles in immune regulation and subsequently affect microbiota components. Finally, our data clarified the described differences between SMAT and LMAT in humans. Conclusions: There were significant differences in cell morphology, gene expression profiles, cell components, biological characteristics, and immune and microbiota regulation roles between regional MATs.

scholarly journals Effect of Sulforaphane and 5-Aza-2’-Deoxycytidine on Melanoma Cell Growth

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 71 ◽  
Author(s):  
Tung-chin Chiang ◽  
Brian Koss ◽  
L. Joseph Su ◽  
Charity L. Washam ◽  
Stephanie D. Byrum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Growth ◽  
Gene Transcription ◽  
Melanoma Cell ◽  
Dna Methyltransferase ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Epigenetic Modifications ◽  
Driving Mechanism ◽  
Epigenetic Drug

Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine—C-C motif ligand 5 (CCL-5)—was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth.

scholarly journals RNAseq Studies Reveal Distinct Transcriptional Response to Vitamin a (VA) Deficiency in Small Intestine (SI) versus Colon, Discovering Novel VA-regulated Genes (P15-002-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Zhi Chai ◽  
Yafei Lyu ◽  
Qiuyan Chen ◽  
Cheng-Hsin Wei ◽  
Lindsay Snyder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Intestine ◽  
Vitamin A ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Differentially Expressed Gene ◽  
Gene Expression Profiles ◽  
Illumina Hiseq ◽  
The Impact

Abstract Objectives To characterize and compare the impact of vitamin A (VA) deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. Methods vitamin A deficient (VAD) mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. Total mRNA extracted from SI and colon were sequenced using Illumina HiSeq 2500 platform. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression patterns and co-expression patterns. Results The comparison between vitamin A sufficient (VAS) and VAD groups detected 49 and 94 DEGs in SI and colon, respectively. According to GO information, DEGs in the SI demonstrated significant enrichment in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, such as “humoral immune response” and “complement activation,” were positively associated with VA in SI. On the contrary, in colon, “cell division” was the only enriched category and was negatively associated with VA. WGCNA identified modules significantly correlated with VA status in SI and in colon. One of those modules contained five known retinoic acid targets. Therefore we have prioritized the other module members (e.g., Mbl2, Mmp9, Mmp13, Cxcl14 and Pkd1l2) to be investigated as candidate genes regulated by VA. Comparison of co-expression modules between SI and colon indicated distinct VA effects on these two organs. Conclusions The results show that VA deficiency alters the gene expression profiles in SI and colon quite differently. Some immune-related genes (Mbl2, Mmp9, Mmp13, Cxcl14 and Pkd1l2) may be novel targets under the control of VA in SI. Funding Sources NIH training grant and NIH research grant. Supporting Tables, Images and/or Graphs

scholarly journals PCA-based unsupervised feature extraction for gene expression analysis of COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kota Fujisawa ◽  
Mamoru Shimo ◽  
Y.-H. Taguchi ◽  
Shinya Ikematsu ◽  
Ryota Miyata
Keyword(s):  
Gene Expression ◽  
Feature Extraction ◽  
Target Genes ◽  
Gene Selection ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Principal Component ◽  
Data Set ◽  
Immune Related Genes ◽  
Unsupervised Feature Extraction

AbstractCoronavirus disease 2019 (COVID-19) is raging worldwide. This potentially fatal infectious disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the complete mechanism of COVID-19 is not well understood. Therefore, we analyzed gene expression profiles of COVID-19 patients to identify disease-related genes through an innovative machine learning method that enables a data-driven strategy for gene selection from a data set with a small number of samples and many candidates. Principal-component-analysis-based unsupervised feature extraction (PCAUFE) was applied to the RNA expression profiles of 16 COVID-19 patients and 18 healthy control subjects. The results identified 123 genes as critical for COVID-19 progression from 60,683 candidate probes, including immune-related genes. The 123 genes were enriched in binding sites for transcription factors NFKB1 and RELA, which are involved in various biological phenomena such as immune response and cell survival: the primary mediator of canonical nuclear factor-kappa B (NF-κB) activity is the heterodimer RelA-p50. The genes were also enriched in histone modification H3K36me3, and they largely overlapped the target genes of NFKB1 and RELA. We found that the overlapping genes were downregulated in COVID-19 patients. These results suggest that canonical NF-κB activity was suppressed by H3K36me3 in COVID-19 patient blood.

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