scholarly journals Promoter Hypermethylation Promotes the Binding of Transcription Factor NFATc1, Triggering Oncogenic Gene Activation in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4569
Author(s):  
Yenan Wu ◽  
Lea Kröller ◽  
Beiping Miao ◽  
Henning Boekhoff ◽  
Andrea S. Bauer ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Activation ◽  
Promoter Hypermethylation ◽  
Ductal Adenocarcinoma ◽  
Promoter Regions ◽  
Functional Studies ◽  
Computational Analyses ◽  
Oncogenic Gene ◽  
Was Gene

Studies have indicated that some genes involved in carcinogenesis are highly methylated in their promoter regions but nevertheless strongly transcribed. It has been proposed that transcription factors could bind specifically to methylated promoters and trigger transcription. We looked at this rather comprehensively for pancreatic ductal adenocarcinoma (PDAC) and studied some cases in more detail. Some 2% of regulated genes in PDAC exhibited higher transcription coupled to promoter hypermethylation in comparison to healthy tissue. Screening 661 transcription factors, several were found to bind specifically to methylated promoters, in particular molecules of the NFAT family. One of them—NFATc1—was substantially more strongly expressed in PDAC than control tissue and exhibited a strong oncogenic role. Functional studies combined with computational analyses allowed determining affected genes. A prominent one was gene ALDH1A3, which accelerates PDAC metastasis and correlates with a bad prognosis. Further studies confirmed the direct up-regulation of ALDH1A3 transcription by NFATc1 promoter binding in a methylation-dependent process, providing insights into the oncogenic role of transcription activation in PDAC that is promoted by DNA methylation.

scholarly journals NF-κB/Rel Transcription Factors in Pancreatic Cancer: Focusing on RelA, c-Rel, and RelB

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 937 ◽  
Author(s):  
Derya Kabacaoglu ◽  
Dietrich A. Ruess ◽  
Jiaoyu Ai ◽  
Hana Algül
Keyword(s):  
Transcription Factors ◽  
Ductal Adenocarcinoma ◽  
Cell Type ◽  
Dual Nature ◽  
Ability To Act ◽  
Cell Type Specific ◽  
Additional Tumor ◽  
Light Chain Enhancer ◽  
Oncogenic Function

Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells in which every single component shows heterogenic effects. Whereas many studies highlighted a per se oncogenic function for NF-κB/Rel TFs across cancers, recent advances in the field revealed their additional tumor-suppressive nature. Specifically, pancreatic ductal adenocarcinoma (PDAC), as one of the deadliest malignant diseases, shows aberrant canonical-noncanonical NF-κB signaling activity. Although decades of work suggest a prominent oncogenic activity of NF-κB signaling in PDAC, emerging evidence points to the opposite including anti-tumor effects. Considering the dual nature of NF-κB signaling and how it is closely linked to many other cancer related signaling pathways, it is essential to dissect the roles of individual Rel TFs in pancreatic carcinogenesis and tumor persistency and progression. Here, we discuss recent knowledge highlighting the role of Rel TFs RelA, RelB, and c-Rel in PDAC development and maintenance. Next to providing rationales for therapeutically harnessing Rel TF function in PDAC, we compile strategies currently in (pre-)clinical evaluation.

scholarly journals Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8460
Author(s):  
Min Young Kim ◽  
Bowen Yan ◽  
Suming Huang ◽  
Yi Qiu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Gene Activation ◽  
Bhlh Transcription Factor ◽  
Nucleosome Remodeling ◽  
Hdac Activity ◽  
Histone Deacetylase 1

Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance.

Screen for CACNA1A and ATP1A2 Mutations in Sporadic Hemiplegic Migraine Patients

Cephalalgia ◽  
2008 ◽  
Vol 28 (9) ◽  
pp. 914-921 ◽  
Author(s):  
LL Thomsen ◽  
E Oestergaard ◽  
A Bjornsson ◽  
H Stefansson ◽  
AC Fasquel ◽  
...  
Keyword(s):  
Population Based ◽  
Causal Role ◽  
Danish Population ◽  
Promoter Regions ◽  
Hemiplegic Migraine ◽  
Functional Studies ◽  
Dna Variants ◽  
Atp1a2 Gene ◽  
Cacna1a Gene

The aim of this study was to investigate the involvement of the CACNA1A and ATP1A2 gene in a population-based sample of sporadic hemiplegic migraine (SHM). Patients with SHM ( n = 105) were identified in a nationwide search in the Danish population. We sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients with SHM to search for possible SHM mutations. Novel DNA variants were discovered in eight SHM patients, four in exons of the CACNA1A gene and four in exons of the ATP1A2 gene. Six of the variants were considered non-pathogenic. The causal role of the two remaining DNA variants is unknown until functional studies have been made or independent genetic evidence is discovered. Only very few DNA variants were identified in 100 SHM patients, and regardless of whether the identified variants are causal the CACNA1A and ATP1A2 genes are not major genes in SHM.

scholarly journals Regulation of the MEF2 Family of Transcription Factors by p38

1999 ◽  
Vol 19 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Ming Zhao ◽  
Liguo New ◽  
Vladimir V. Kravchenko ◽  
Yutaka Kato ◽  
Hermann Gram ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Promoter Regions ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Group Members ◽  
Map Kinase Pathway ◽  
Kinase Signaling Pathway

ABSTRACT Members of the MEF2 family of transcription factors bind as homo- and heterodimers to the MEF2 site found in the promoter regions of numerous muscle-specific, growth- or stress-induced genes. We showed previously that the transactivation activity of MEF2C is stimulated by p38 mitogen-activated protein (MAP) kinase. In this study, we examined the potential role of the p38 MAP kinase pathway in regulating the other MEF2 family members. We found that MEF2A, but not MEF2B or MEF2D, is a substrate for p38. Among the four p38 group members, p38 is the most potent kinase for MEF2A. Threonines 312 and 319 within the transcription activation domain of MEF2A are the regulatory sites phosphorylated by p38. Phosphorylation of MEF2A in a MEF2A-MEF2D heterodimer enhances MEF2-dependent gene expression. These results demonstrate that the MAP kinase signaling pathway can discriminate between different MEF2 isoforms and can regulate MEF2-dependent genes through posttranslational activation of preexisting MEF2 protein.

scholarly journals Evolutionary and Characteristic Analysis of RING-DUF1117 E3 Ubiquitin Ligase Genes in Gossypium Discerning the Role of GhRDUF4D in Verticillium dahliae Resistance

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1145
Author(s):  
Yan-Peng Zhao ◽  
Jian-Ling Shen ◽  
Wen-Jie Li ◽  
Na Wu ◽  
Chen Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Verticillium Dahliae ◽  
Virus Induced Gene Silencing ◽  
Characteristic Analysis ◽  
Functional Studies ◽  
Drought And Salt Stress ◽  
Domain Of Unknown Function ◽  
New Gene ◽  
Insight Into

Verticillium wilt, primarily induced by the soil-borne fungus Verticillium dahliae, is a serious threat to cotton fiber production. There are a large number of really interesting new gene (RING) domain-containing E3 ubiquitin ligases in Arabidopsis, of which three (At2g39720 (AtRHC2A), At3g46620 (AtRDUF1), and At5g59550 (AtRDUF2)) have a domain of unknown function (DUF) 1117 domain in their C-terminal regions. This study aimed to detect and characterize the RDUF members in cotton, to gain an insight into their roles in cotton’s adaptation to environmental stressors. In this study, a total of 6, 7, 14, and 14 RDUF (RING-DUF1117) genes were detected in Gossypium arboretum, G. raimondii, G. hirsutum, and G. barbadense, respectively. These RDUF genes were classified into three groups. The genes in each group were highly conserved based on gene structure and domain analysis. Gene duplication analysis revealed that segmental duplication occurred during cotton evolution. Expression analysis revealed that the GhRDUF genes were widely expressed during cotton growth and under abiotic stresses. Many cis-elements related to hormone response and environment stressors were identified in GhRDUF promoters. The predicted target miRNAs and transcription factors implied that GhRDUFs might be regulated by gra-miR482c, as well as by transcription factors, including MYB, C2H2, and Dof. The GhRDUF genes responded to cold, drought, and salt stress and were sensitive to jasmonic acid, salicylic acid, and ethylene signals. Meanwhile, GhRDUF4D expression levels were enhanced after V. dahliae infection. Subsequently, GhRDUF4D was verified by overexpression in Arabidopsis and virus-induced gene silencing treatment in upland cotton. We observed that V. dahliae resistance was significantly enhanced in transgenic Arabidopsis, and weakened in GhRDUF4D silenced plants. This study conducted a comprehensive analysis of the RDUF genes in Gossypium, hereby providing basic information for further functional studies.

DNA methylation events in transcription factors and gene expression changes in colon cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1593-1610
Author(s):  
Anna Díez-Villanueva ◽  
Rebeca Sanz-Pamplona ◽  
Robert Carreras-Torres ◽  
Ferran Moratalla-Navarro ◽  
M Henar Alonso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Colon Cancer ◽  
Transcription Factors ◽  
Target Genes ◽  
Linear Models ◽  
Cpg Islands ◽  
Promoter Regions ◽  
Differential Gene

Aim: Gain insight about the role of DNA methylation in the malignant growth of colon cancer. Patients & methods: Methylation and gene expression from 90 adjacent-tumor paired tissues and 48 healthy tissues were analyzed. Tumor genes whose change in expression was explained by changes in methylation were identified using linear models adjusted for tumor stromal content. Results: No differences in methylation were found between adjacent and healthy tissues, but clear differences were found between adjacent and tumor samples. We identified hypermethylated CpG islands located in promoter regions that drive differential gene expression of transcription factors and their target genes. Conclusion: Changes in methylation of a few genes provoke important changes in gene expression, by expanding the signal through transcription activation/repression.

Pancreatic Ductal Adenocarcinoma and Transcription Factors: Role of c-Myc

2011 ◽  
Vol 42 (2) ◽  
pp. 76-84 ◽  
Author(s):  
Anouchka Skoudy ◽  
Inmaculada Hernández-Muñoz ◽  
Pilar Navarro
Keyword(s):  
Transcription Factors ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals The Role of lncRNAs in the Stem Phenotype of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6374
Author(s):  
Jorge Melendez-Zajgla ◽  
Vilma Maldonado
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Negative Effects ◽  
Tissue Microenvironment ◽  
Non Coding Rnas

Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC).

scholarly journals The role of FOSL1 in stem-like cell reprogramming processes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Valeria Pecce ◽  
Antonella Verrienti ◽  
Giulia Fiscon ◽  
Marialuisa Sponziello ◽  
Federica Conte ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Cancer Progression ◽  
In Vitro Study ◽  
Therapy Resistance ◽  
Promoter Regions ◽  
Matrix Component ◽  
Metastatic Growth

AbstractCancer stem-like cells (CSCs) have self-renewal abilities responsible for cancer progression, therapy resistance, and metastatic growth. The glioblastoma stem-like cells are the most studied among CSC populations. A recent study identified four transcription factors (SOX2, SALL2, OLIG2, and POU3F2) as the minimal core sufficient to reprogram differentiated glioblastoma (GBM) cells into stem-like cells. Transcriptomic data of GBM tissues and cell lines from two different datasets were then analyzed by the SWItch Miner (SWIM), a network-based software, and FOSL1 was identified as a putative regulator of the previously identified minimal core. Herein, we selected NTERA-2 and HEK293T cells to perform an in vitro study to investigate the role of FOSL1 in the reprogramming mechanisms. We transfected the two cell lines with a constitutive FOSL1 cDNA plasmid. We demonstrated that FOSL1 directly regulates the four transcription factors binding their promoter regions, is involved in the deregulation of several stemness markers, and reduces the cells’ ability to generate aggregates increasing the extracellular matrix component FN1. Although further experiments are necessary, our data suggest that FOSL1 reprograms the stemness by regulating the core of the four transcription factors.

Ionic homeostasis and subcellular element compartmentation

1990 ◽  
Vol 48 (2) ◽  
pp. 150-151
Author(s):  
Ann LeFurgey ◽  
Peter Ingram ◽  
J.J. Blum ◽  
M.C. Carney ◽  
L.A. Hawkey ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Ionic Homeostasis ◽  
X Ray ◽  
Functional Studies ◽  
Cell Compartments ◽  
X Ray Imaging ◽  
Resolution Electron ◽  
Multiple Cell ◽  
Role Of Zn

Subcellular compartments commonly identified and analyzed by high resolution electron probe x-ray microanalysis (EPXMA) include mitochondria, cytoplasm and endoplasmic or sarcoplasmic reticulum. These organelles and cell regions are of primary importance in regulation of cell ionic homeostasis. Correlative structural-functional studies, based on the static probe method of EPXMA combined with biochemical and electrophysiological techniques, have focused on the role of these organelles, for example, in maintaining cell calcium homeostasis or in control of excitation-contraction coupling. New methods of real time quantitative x-ray imaging permit simultaneous examination of multiple cell compartments, especially those areas for which both membrane transport properties and element content are less well defined, e.g. nuclei including euchromatin and heterochromatin, lysosomes, mucous granules, storage vacuoles, microvilli. Investigations currently in progress have examined the role of Zn-containing polyphosphate vacuoles in the metabolism of Leishmania major, the distribution of Na, K, S and other elements during anoxia in kidney cell nuclel and lysosomes; the content and distribution of S and Ca in mucous granules of cystic fibrosis (CF) nasal epithelia; the uptake of cationic probes by mltochondria in cultured heart ceils; and the junctional sarcoplasmic retlculum (JSR) in frog skeletal muscle.

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