scholarly journals SMAD4 Feedback Activates the Canonical TGF-β Family Signaling Pathways

2021 ◽  
Vol 22 (18) ◽  
pp. 10024
Author(s):  
Lu Liu ◽  
Qiqi Li ◽  
Liu Yang ◽  
Qifa Li ◽  
Xing Du
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Epigenetic Regulation ◽  
Granulosa Cells ◽  
Regulatory Mechanism ◽  
Genetic Regulation ◽  
Feedback Regulation ◽  
Core Promoters ◽  
The Core ◽  
First Time

TGF-β family signaling pathways, including TGF-β and BMP pathways, are widely involved in the regulation of health and diseases through downstream SMADs, which are also regulated by multiple validated mechanisms, such as genetic regulation, epigenetic regulation, and feedback regulation. However, it is still unclear whether R-SMADs or Co-SMAD can feedback regulate the TGF-β family signaling pathways in granulosa cells (GCs). In this study, we report a novel mechanism underlying the feedback regulation of TGF-β family signaling pathways, i.e., SMAD4, the only Co-SMAD, positive feedback activates the TGF-β family signaling pathways in GCs with a basal level of TGF-β ligands by interacting with the core promoters of its upstream receptors. Mechanistically, SMAD4 acts as a transcription factor, and feedback activates the transcription of its upstream receptors, including ACVR1B, BMPR2, and TGFBR2, of the canonical TGF-β signaling pathways by interacting with three coactivators (c-JUN, CREB1, and SP1), respectively. Notably, three different interaction modes between SMAD4 and coactivators were identified in SMAD4-mediated feedback regulation of upstream receptors through reciprocal ChIP assays. Our findings in the present study indicate for the first time that SMAD4 feedback activates the canonical TGF-β family signaling pathways in GCs, which improves and expands the regulatory mechanism, especially the feedback regulation modes of TGF-β family signaling pathways in ovarian GCs.

scholarly journals SMAD4 Feedback Activates The Canonical TGF-β Family Signaling Pathways

2021 ◽  
Author(s):  
Xing Du ◽  
Qiqi Li ◽  
Liu Yang ◽  
Qifa Li
Keyword(s):  
Signaling Pathways ◽  
Core Promoter ◽  
Genetic Regulation ◽  
Feedback Regulation ◽  
Bmp Signaling ◽  
The Core ◽  
Porcine Granulosa Cells ◽  
Health And Disease ◽  
And Function

Abstract Background: TGF-β family signaling pathways, including TGF-β and BMP signaling pathways, are widely involved in the regulation of health and disease, which are also regulated by multiple validated mechanisms, such as genetic regulation, epigenetic regulation, and feedback regulation. The objective of this research is to investigate the molecular mechanism and function mode of SMAD4 directly feedback regulation of TGF-β family signaling pathways in porcine granulosa cells (GC).Results: The transcriptomic alteration of porcine GCs induced by SMAD4 silencing was re-analyzed with the background of Sus scrofa RefSeq 11.1 (Sscrofa 11.1). A total of 986 differentially expressed mRNAs (DEmRNAs) were identified, including 467 down-regulated and 519 up-regulated genes. Functional assessment showed the impacts of DEmRNAs on the regulation of states and function of GCs, and the oocyte development. As the upstream receptors of SMAD4, ACVR1B, BMPR2, and TGFBR2 were selected from down-regulated DEmRNAs for further research. In vitro, qRT-PCR and western blotting were performed and confirmed that SMAD4 significantly induced the expression of ACVR1B, BMPR2, and TGFBR2 in porcine GCs. Besides, RACE and luciferase activity assays were carried out to identified the core promoter of porcine ACVR1B, BMPR2, and TGFBR2. Results from ChIP assays showed that SMAD4 directly binds to the SMAD4 binding elements (SBEs) within the core promoter of its upstream receptors by acting as a transcription factor. Furthermore, c-JUN, CREB1, and SP1 were identified as SMAD4-interacted co-activators by IP assays and inhibition of which could dramatically suppress the expression of porcine ACVR1B, BMPR2, and TGFBR2 that induced by SMAD4 over-expression. Furthermore, three different interaction modes between SMAD4 and co-activators were identified by reciprocal ChIP assays.Conclusions: Take together, our findings revealed a novel feedback regulatory mechanism of TGF-β family signaling pathways in porcine GCs, and demonstrated for the first time that SMAD4, the only Co-SMAD, directly feedback activates the transcription of canonical TGF-β family signaling pathway receptors by interacting with three co-activators in different modes, which improves and expands the regulatory network, especially the feedback regulation modes of TGF-β family signaling pathways in the ovary.

Predicting Polymerase II Core Promoters by Cooperating Transcription Factor Binding Sites in Eukaryotic Genes

2004 ◽  
Vol 36 (4) ◽  
pp. 250-258 ◽  
Author(s):  
Xiao-Tu Ma ◽  
Min-Ping Qian ◽  
Hai-Xu Tang
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Core Promoter ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Upstream Gene ◽  
Core Promoters ◽  
Factor Binding ◽  
The Core ◽  
Eukaryotic Genes

Abstract Several discriminate functions for predicting core promoters that based on the potential cooperation between transcription factor binding sites (TFBSs) are discussed. It is demonstrated that the promoter predicting accuracy is improved when the cooperation among TFBSs is taken into consideration. The core promoter region of a newly discovered gene CKLFSF1 is predicted to locate more than 1.5 kb far away from the 5′ end of the transcript and in the last intron of its upstream gene, which is experimentally confirmed later. The core promoters of 3402 human RefSeq sequences, obtained by extending the mRNAs in human genome sequences, are predicted by our algorithm, and there are about 60% of the predicted core promoters locating within the ± 500 bp region relative to the annotated transcription start site.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

scholarly journals Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jakob Weglage ◽  
Friederike Wolters ◽  
Laura Hehr ◽  
Jakob Lichtenberger ◽  
Celina Wulz ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Colorectal Carcinogenesis ◽  
Sub Saharan Africa ◽  
Interleukin 4 ◽  
Health Burden ◽  
Sub Saharan ◽  
Considerable Morbidity ◽  
First Time

AbstractSchistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

scholarly journals Challenges with Methods for Detecting and Studying the Transcription Factor Nuclear Factor Kappa B (NF-κB) in the Central Nervous System

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1335
Author(s):  
Marina Mostafizar ◽  
Claudia Cortes-Pérez ◽  
Wanda Snow ◽  
Jelena Djordjevic ◽  
Aida Adlimoghaddam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Quantitative Methods ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Responses ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Regulated Gene Expression ◽  
Transcription Factor Nuclear Factor

The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammation and host defense. Thus, an understanding of the methodological issues around its detection for localization, quantification, and mechanistic insights should have a broad interest across the molecular neuroscience community. In this review, we summarize the available methods for the proper detection and analysis of NF-κB among various brain tissues, cell types, and subcellular compartments, using both qualitative and quantitative methods. We also summarize the flexibility and performance of these experimental methods for the detection of the protein, accurate quantification in different samples, and the experimental challenges in this regard, as well as suggestions to overcome common challenges.

scholarly journals On the formation and stability of fermionic dark matter halos in a cosmological framework

2020 ◽  
Author(s):  
Carlos R Argüelles ◽  
Manuel I Díaz ◽  
Andreas Krut ◽  
Rafael Yunis
Keyword(s):  
Black Hole ◽  
Dark Matter ◽  
Space Distribution ◽  
Coarse Grained ◽  
Dark Matter Halos ◽  
The Core ◽  
The Galaxy ◽  
Gravitating Systems ◽  
The Given ◽  
First Time

Abstract The formation and stability of collisionless self-gravitating systems is a long standing problem, which dates back to the work of D. Lynden-Bell on violent relaxation, and extends to the issue of virialization of dark matter (DM) halos. An important prediction of such a relaxation process is that spherical equilibrium states can be described by a Fermi-Dirac phase-space distribution, when the extremization of a coarse-grained entropy is reached. In the case of DM fermions, the most general solution develops a degenerate compact core surrounded by a diluted halo. As shown recently, the latter is able to explain the galaxy rotation curves while the DM core can mimic the central black hole. A yet open problem is whether this kind of astrophysical core-halo configurations can form at all, and if they remain stable within cosmological timescales. We assess these issues by performing a thermodynamic stability analysis in the microcanonical ensemble for solutions with given particle number at halo virialization in a cosmological framework. For the first time we demonstrate that the above core-halo DM profiles are stable (i.e. maxima of entropy) and extremely long lived. We find the existence of a critical point at the onset of instability of the core-halo solutions, where the fermion-core collapses towards a supermassive black hole. For particle masses in the keV range, the core-collapse can only occur for Mvir ≳ E9M⊙ starting at zvir ≈ 10 in the given cosmological framework. Our results prove that DM halos with a core-halo morphology are a very plausible outcome within nonlinear stages of structure formation.

scholarly journals Plant Hormone Metabolome and Transcriptome Analysis of Dwarf and Wild-type Banana

2021 ◽  
Author(s):  
Biao Deng ◽  
Xuan Wang ◽  
Xing Long ◽  
Ren Fang ◽  
Shuangyun Zhou ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Transcriptome Analysis ◽  
Regulatory Mechanism ◽  
Feedback Regulation ◽  
Wild Type ◽  
Hormone Levels ◽  
Transporter Protein ◽  
Repressor Proteins ◽  
Differential Gene ◽  
The Relationship

AbstractGibberellin (GA), auxin (IAA) and brassinosteroid (BR) are indispensable in the process of plant growth and development. Currently, research on the regulatory mechanism of phytohormones in banana dwarfism is mainly focused on GA, and few studies are focused on IAA and BR. In this study, we measured the contents of endogenous GA, IAA and BR and compared the transcriptomes of wild-type Williams banana and its dwarf mutant across five successive growth periods. We investigated the relationship between hormones and banana dwarfism and explored differential gene expression through transcriptome analysis, thus revealing the possible metabolic regulatory mechanism. We inferred a complex regulatory network of banana dwarfing. In terms of endogenous hormone levels, GA and IAA had significant effects on banana dwarfing, while BR had little effect. The key gene in GA biosynthesis of is GA2ox, and the key genes in IAA biosynthesis are TDC and YUCCA. The differential expression of these genes might be the main factor affecting hormone levels and plant height. In terms of hormone signal transduction, DELLA and AUX/IAA repressor proteins were the core regulators of GA and IAA, respectively. They inhibited the process of signal transduction and had feedback regulation on hormone levels. Finally, the transporter protein PIN, AUX1/LAX protein family and ABCB subfamily played supplementary roles in the transport of IAA. These results provide new insights into GA and IAA regulation of banana growth and a reliable foundation for the improvement of dwarf varieties.

scholarly journals The Regulatory Mechanism of Water Activities on Aflatoxins Biosynthesis and Conidia Development, and Transcription Factor AtfB Is Involved in This Regulation

Toxins ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 431
Author(s):  
Longxue Ma ◽  
Xu Li ◽  
Xiaoyun Ma ◽  
Qiang Yu ◽  
Xiaohua Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Environmental Factors ◽  
Health Risks ◽  
Sexual Development ◽  
Regulatory Mechanism ◽  
Food Storage ◽  
Economic Losses ◽  
Transcriptional Level ◽  
Conidia Production

Peanuts are frequently infected by Aspergillus strains and then contaminated by aflatoxins (AF), which brings out economic losses and health risks. AF production is affected by diverse environmental factors, especially water activity (aw). In this study, A. flavus was inoculated into peanuts with different aw (0.90, 0.95, and 0.99). Both AFB1 yield and conidia production showed the highest level in aw 0.90 treatment. Transcriptional level analyses indicated that AF biosynthesis genes, especially the middle- and later-stage genes, were significantly up-regulated in aw 0.90 than aw 0.95 and 0.99. AtfB could be the pivotal regulator response to aw variations, and could further regulate downstream genes, especially AF biosynthesis genes. The expressions of conidia genes and relevant regulators were also more up-regulated at aw 0.90 than aw 0.95 and 0.99, suggesting that the relative lower aw could increase A. flavus conidia development. Furthermore, transcription factors involved in sexual development and nitrogen metabolism were also modulated by different aw. This research partly clarified the regulatory mechanism of aw on AF biosynthesis and A. flavus development and it would supply some advice for AF prevention in food storage.

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