scholarly journals Tissue-Specific Transgenic Knockdown of Fos-Related Antigen 2 (Fra-2) Expression Mediated by Dominant Negative Fra-2

2001 ◽  
Vol 21 (11) ◽  
pp. 3704-3713 ◽  
Author(s):  
Martin Smith ◽  
Zoe Burke ◽  
Ann Humphries ◽  
Tim Wells ◽  
David Klein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pineal Gland ◽  
Target Genes ◽  
Second Messengers ◽  
Regulatory Region ◽  
Dominant Negative ◽  
Transgenic Rat ◽  
Iodothyronine Deiodinase ◽  
Protein Levels ◽  
Genes Encoding

ABSTRACT Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-early genes, most of which are rapidly induced by second messengers. All members of this family act by binding to AP-1 sites as heterodimeric complexes with other proteins. However, each appears to have a distinct role. The role and biology of Fra-2 are less well understood than those of its relatives c-Fos, Fra-1, and FosB; moreover, Fra-2 target genes remain largely unknown, as does the basis of its selective effects on transcriptional activity. To pursue these issues, we created a transgenic rat line (NATDNF2) in which a dominant negative fra-2 (DNF2) gene is strongly expressed in the pineal gland; tissue selectivity was achieved by putting the DNF2 gene under the control of the rat arylalkylamineN-acetyltransferase (AANAT) regulatory region, which targets gene expression to a very restricted set of tissues (pineal gland ≫ retina). Expression of AANAT is normally turned on after the onset of darkness in the rat; as a result, pineal DNF2 expression occurs only at night. This was associated with marked suppression of the nocturnal increase in fra-2 mRNA and protein levels, indicating that DNF2 expression inhibits downstream effects of Fra-2, including the maintenance of high levels offra-2 gene expression. Analysis of 1,190 genes in the NATDNF2 pineal gland, including the AANAT gene, identified two whose expression is strongly linked to fra-2 expression: the genes encoding type II iodothyronine deiodinase and nectadrin (CD24).

scholarly journals Alterations of mesenchymal stromal cells in cerebrospinal fluid: insights from transcriptomics and an ALS clinical trial

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ashley A. Krull ◽  
Deborah O. Setter ◽  
Tania F. Gendron ◽  
Sybil C. L. Hrstka ◽  
Michael J. Polzin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebrospinal Fluid ◽  
Growth Factors ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Large Scale ◽  
Therapeutic Benefit ◽  
Protein Levels ◽  
Genes Encoding ◽  
Intrathecal Space

Abstract Background Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases. Methods In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS). Results Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs. Conclusions Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.

Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen

Development ◽  
1998 ◽  
Vol 125 (21) ◽  
pp. 4185-4193 ◽  
Author(s):  
Q. Gao ◽  
R. Finkelstein
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Repeated Sequence ◽  
Drosophila Embryo ◽  
Sequence Motif ◽  
Specific Expression ◽  
Gap Gene

The Bicoid (Bcd) morphogen establishes the head and thorax of the Drosophila embryo. Bcd activates the transcription of identified target genes in the thoracic segments, but its mechanism of action in the head remains poorly understood. It has been proposed that Bcd directly activates the cephalic gap genes, which are the first zygotic genes to be expressed in the head primordium. It has also been suggested that the affinity of Bcd-binding sites in the promoters of Bcd target genes determines the posterior extent of their expression (the Gene X model). However, both these hypotheses remain untested. Here, we show that a small regulatory region upstream of the cephalic gap gene orthodenticle (otd) is sufficient to recapitulate early otd expression in the head primordium. This region contains two control elements, each capable of driving otd-like expression. The first element has consensus Bcd target sites that bind Bcd in vitro and are necessary for head-specific expression. As predicted by the Gene X model, this element has a relatively low affinity for Bcd. Surprisingly, the second regulatory element has no Bcd sites. Instead, it contains a repeated sequence motif similar to a regulatory element found in the promoters of otd-related genes in vertebrates. Our study is the first demonstration that a cephalic gap gene is directly regulated by Bcd. However, it also shows that zygotic gene expression can be targeted to the head primordium without direct Bcd regulation.

scholarly journals Treatment with PPARαAgonist Clofibrate Inhibits the Transcription and Activation of SREBPs and Reduces Triglyceride and Cholesterol Levels in Liver of Broiler Chickens

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Lijun Zhang ◽  
Chunyan Li ◽  
Fang Wang ◽  
Shenghua Zhou ◽  
Mingjun Shangguan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Broiler Chickens ◽  
Target Genes ◽  
Nuclear Protein ◽  
Mrna Level ◽  
Control Group ◽  
Mrna Levels ◽  
Protein Levels ◽  
Cholesterol Levels ◽  
Regulation Mechanisms

PPARαagonist clofibrate reduces cholesterol and fatty acid concentrations in rodent liver by an inhibition of SREBP-dependent gene expression. In present study we investigated the regulation mechanisms of the triglyceride- and cholesterol-lowering effect of the PPARαagonist clofibrate in broiler chickens. We observed that PPARαagonist clofibrate decreases the mRNA and protein levels of LXRαand the mRNA and both precursor and nuclear protein levels of SREBP1 and SREBP2 as well as the mRNA levels of the SREBP1 (FASNandGPAM) and SREBP2 (HMGCRandLDLR) target genes in the liver of treated broiler chickens compared to control group, whereas the mRNA level ofINSIG2, which inhibits SREBP activation, was increased in the liver of treated broiler chickens compared to control group. Taken together, the effects of PPARαagonist clofibrate on lipid metabolism in liver of broiler chickens involve inhibiting transcription and activation of SREBPs and SREBP-dependent lipogenic and cholesterologenic gene expression, thereby resulting in a reduction of the triglyceride and cholesterol levels in liver of broiler chickens.

scholarly journals Nrf Transcription Factors in Keratinocytes Are Essential for Skin Tumor Prevention but Not for Wound Healing

2006 ◽  
Vol 26 (10) ◽  
pp. 3773-3784 ◽  
Author(s):  
Ulrich auf dem Keller ◽  
Marcel Huber ◽  
Tobias A. Beyer ◽  
Angelika Kümin ◽  
Christina Siemes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Wound Repair ◽  
Target Genes ◽  
Dominant Negative ◽  
Skin Tumor ◽  
Cellular Stress Response ◽  
Skin Development

ABSTRACT The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. We provide evidence that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. Our results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ.

The dominant negative thyroid hormone receptor β-mutant Δ337T alters PPARα signaling in heart

2007 ◽  
Vol 292 (2) ◽  
pp. E453-E460 ◽  
Author(s):  
Norman E. Buroker ◽  
Martin E. Young ◽  
Caimiao Wei ◽  
Kyle Serikawa ◽  
Ming Ge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Protein Content ◽  
Nuclear Receptors ◽  
Cross Talk ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Variable Cross ◽  
Multiple Genes

PPARα and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPARα regulation of target genes and used mice exhibiting a cardioselective Δ337T TRβ1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TRα and TRβ. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic (MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPARα ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPARα, TRα2, RXRβ, or PGC-1α. However, protein content for TRα1 and the PPARα heterodimeric partner RXRα was diminished in MUT, whereas PPARβ increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The non-ligand-binding TRβ1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPARα ligands may be determined by thyroid hormone state and TR function.

scholarly journals Enhancement of renin and prorenin receptor in collecting duct of Cyp1a1-Ren2 rats may contribute to development and progression of malignant hypertension

2011 ◽  
Vol 300 (2) ◽  
pp. F581-F588 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Dustyn E. Williams ◽  
Liu Liu ◽  
Kimberly L. Kavanagh ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Collecting Duct ◽  
Normal Diet ◽  
Malignant Hypertension ◽  
Soluble Form ◽  
Transgenic Rat ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Prorenin Receptor

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats ( n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.

scholarly journals Two functionally redundant FK506-binding proteins regulate multidrug resistance gene expression and govern azole antifungal resistance

2021 ◽  
Author(s):  
Romila Moirangthem ◽  
Kundan Kumar ◽  
Rupinder Kaur
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Target Genes ◽  
Fungal Infections ◽  
Antifungal Resistance ◽  
Azole Resistance ◽  
Multidrug Resistance Gene ◽  
Protein Levels ◽  
Fk506 Binding Proteins

Increasing resistance to antifungal therapy is an impediment to effective treatment of fungal infections. Candida glabrata is an opportunistic human fungal pathogen which is inherently less susceptible to cost-effective azole antifungals. Gain-of-function mutations in the Zn-finger pleiotropic drug resistance transcriptional activator-encoding gene, CgPDR1, are the most prevalent cause of azole resistance in clinical settings. CgPDR1 is also transcriptionally activated upon azole exposure, however, factors governing CgPDR1 gene expression are not yet fully understood. Here, we have uncovered a novel role for two FK506-binding proteins, CgFpr3 and CgFpr4, in regulation of the CgPDR1 regulon. We show that CgFpr3 and CgFpr4 possess peptidyl-prolyl isomerase domain, and act redundantly to control CgPDR1 expression, as Cgfpr3Δ4Δ mutant displayed elevated expression of CgPDR1 gene, along with overexpression of its target genes, CgCDR1, CgCDR2 and CgSNQ2, that code for ATP-binding cassette multidrug transporters. Further, CgFpr3 and CgFpr4 are required for maintenance of histone H3 and H4 protein levels, and fluconazole exposure leads to elevated H3 and H4 protein levels. Consistent with a role of histone proteins in azole resistance, disruption of genes coding for the histone demethylase CgRph1 and histone H3K36-specific methyltransferase CgSet2 leads to increased and decreased susceptibility to fluconazole, respectively, with Cgrph1Δ mutant displaying significantly lower basal expression of CgPDR1 and CgCDR1 genes. These data underscore a hitherto unknown role of histone methylation in modulating the most common azole antifungal resistance mechanism. Altogether, our findings establish a link between CgFpr-mediated histone homeostasis and CgPDR1 gene expression, and implicate CgFpr in virulence of C. glabrata.

scholarly journals Maternal Resveratrol Supplementation Prevents Cognitive Decline in Senescent Mice Offspring

2019 ◽  
Vol 20 (5) ◽  
pp. 1134 ◽  
Author(s):  
Vanesa Izquierdo ◽  
Verónica Palomera-Ávalos ◽  
Sergio López-Ruiz ◽  
Anna-Maria Canudas ◽  
Mercè Pallàs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Target Genes ◽  
Epigenetic Inheritance ◽  
Mtor Inhibition ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Age Related ◽  
F2 Generation ◽  
Age Related Cognitive Decline

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer’s Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate the beneficial effects of maternal resveratrol supplementation in the direct exposed F1 generation and the transgenerational F2 generation. The offspring was generated from females Senescence Accelerated Mouse-Prone (SAMP8) fed a resveratrol-enriched diet for two months prior to mating. Object novel recognition and Morris Water Maze (MWM) demonstrated improvements in cognition in the 6-month-old F1 and F2 generations from resveratrol fed mothers. A significant increase in global DNA methylation with a decrease in hydroxymethylation in F1 and F2 were found. Accordingly, Dnmt3a/b and Tet2 gene expression changed. Methylation levels of Nrf2 and NF-kβ genes promoters raised in offspring, inducing changes in target genes expression, as well as hydrogen peroxide levels. Offspring that resulted from a resveratrol fed mother showed increase AMPKα activation, mTOR inhibition, and an increase in Pgc-1α gene expression and Beclin-1 protein levels. Endoplasmic reticulum stress sensors were found changed both in F1 and F2 generations. Overall, our results demonstrated that maternal resveratrol supplementation could prevent cognitive impairment in the SAMP8 mice offspring through epigenetic changes and cell signaling pathways.

scholarly journals Search for Candidate Genes Causing the Excessive Ca Accumulation in Roots of Tipburn-Damaged Lisianthus (Eustoma grandiflorum) Cultivars

Agriculture ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 254
Author(s):  
Takanori Kuronuma ◽  
Hitoshi Watanabe
Keyword(s):  
Gene Expression ◽  
Candidate Genes ◽  
Target Genes ◽  
Pectin Methylesterase ◽  
Eustoma Grandiflorum ◽  
Gene Encoding ◽  
Severe Problem ◽  
Horticultural Crops ◽  
Genes Encoding ◽  
Leaves And Roots

Occurrence of tipburn is a severe problem in the production of lisianthus cultivars. Previous studies have shown excessive Ca accumulation in the roots of tipburn-damaged cultivars, where the distribution of Ca to the tips of the top leaves is inhibited. However, few studies have investigated the association between Ca accumulation and gene expression in horticultural crops. To provide a list of candidate target genes that might be causing the excessive Ca accumulation in roots, we focused Ca2+ transporter and pectin methylesterase (PME) genes and RNA-seq of upper leaves and roots in tipburn-occurrence cultivar (“Voyage peach”: VP) and non-occurrence cultivar (“Umi honoka”: UH) was conducted. In both the upper leaves and roots of VP, genes encoding the glutamate receptors (GLRs), cation/Ca2+ exchangers 4 (CCX4), Na+/Ca2+ exchanger-like protein (NCL), and PMEs were upregulated, and a gene encoding the cyclic nucleotide-gated ion channel 9 (CNGC9) was downregulated. In contrast, genes encoding the vacuolar cation/proton exchanger 5 (CAX5), calcium-transporting ATPase 1 and 12 (ACA1 and ACA12) showed differential expression in each organ. Among them, only CAX5 was upregulated and ACA12 was downregulated in the roots of VP. Based on these results, we suggested that CAX5 and ACA12 are the candidate genes causing the excessive Ca accumulation in the roots of tipburn-occurrence lisianthus cultivars. Future studies should investigate the temporal changes in gene expression using quantitative PCR and conduct functional analysis of candidate genes in tipburn-damaged lisianthus cultivars.

scholarly journals Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue

2016 ◽  
Vol 62 (3) ◽  
pp. 283-289 ◽  
Author(s):  
V.V. Miroshnikova ◽  
A.A. Panteleeva ◽  
E.A. Bazhenova ◽  
E.P. Demina ◽  
T.S. Usenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Cholesterol Metabolism ◽  
Nuclear Factor ◽  
Specific Expression ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
And Control

Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis – LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels. ABCA1 and ABCG1 gene expression positively correlated with obesity indicators such as body mass index (BMI) (r=0.522, p=0.004; r=0.594, p=0.001, respectively) and waist circumference (r=0.403, p=0.033; r=0.474, p=0.013, respectively). The development of obesity is associated with decreased IAT levels of RORa and LXRb mRNA (p=0.016 and p=0.002, respectively). These data suggest that the nuclear factor RORa can play a significant role in the regulation of cholesterol metabolism and control IAT expression of ABCA1 and ABCG1, while the level of IAT LXRb gene expression may be an important factor associated with the development of obesity.

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