scholarly journals Expression of Homeobox Gene HLX and its Downstream Target Genes are Altered in Placentae From Discordant Twin Pregnancies

2017 ◽  
Vol 21 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Nicola Yuen ◽  
Shaun P. Brennecke ◽  
Mark P. Umstad ◽  
Hannah E. J. Yong ◽  
Anthony J. Borg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Normal Control ◽  
Fetal Growth ◽  
Target Genes ◽  
Homeobox Gene ◽  
Model Systems ◽  
Downstream Target ◽  
Protein Levels ◽  
Twin Pregnancies ◽  
Discordant Twin

A discordant twin gestation, in which one fetus is significantly growth restricted, compared to the other normal twin, is a unique model that can be used to elucidate the mechanism(s) by which the intrauterine environment affects fetal growth. In many model systems, placental transcription factor genes regulate fetal growth. Transcription factors regulate growth through their activation or repression of downstream target genes that mediate important cell functions. The objective of this study was to determine the expression of the placental HLX homeobox gene transcription factor and its downstream target genes in dizygotic twins with growth discordance. In this cross-sectional study, HLX and its downstream target genes’ retinoblastoma 1 (RB1) and cyclin kinase D (CDKN1C) expression levels were determined in placentae obtained from dichorionic diamniotic twin pregnancies (n = 23) where one of the twins was growth restricted. Fetal growth restriction (FGR) was defined as small for gestational age with abnormal umbilical artery Doppler indices when compared with the normal control co-twin. Homeobox gene HLX expression was significantly decreased at both the mRNA and protein levels in FGR twin placentae compared with the normal control co-twin placentae (p < .05). Downstream target genes CDKN1C and RB1 were also significantly decreased and increased, respectively, at both the mRNA and protein levels in FGR twin placentae compared with normal control co-twin placentae (p < .05). Together, these observations suggest an important association between HLX transcription factor expression and abnormal human placental development in discordant twin pregnancies.

Protective effect of hydralazine on a cellular model of Parkinson’s disease: a possible role of hypoxia-inducible factor (HIF)-1α

2020 ◽  
Vol 98 (3) ◽  
pp. 405-414 ◽  
Author(s):  
Mehrnaz Mehrabani ◽  
Mohammad Hadi Nematollahi ◽  
Mojde Esmaeili Tarzi ◽  
Kobra Bahrampour Juybari ◽  
Moslem Abolhassani ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Antioxidant Power ◽  
Expression Levels ◽  
Downstream Target ◽  
Protein Levels ◽  
Ferric Reducing Antioxidant Power ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disease accompanied by a low expression level of cerebral hypoxia-inducible factor (HIF-1α). Hence, activating the hypoxia-signaling pathway may be a favorable therapeutic approach for curing PD. This study explored the efficacy of hydralazine, a well-known antihypertensive agent, for restoring the impaired HIF-1 signaling in PD, with the aid of 6-hydroxydopamine (6-OHDA)-exposed SH-SY5Y cells. The cytotoxicity of hydralazine and 6-OHDA on the SH-SY5Y cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and apoptosis detection assays. The activities of malondialdehyde, nitric oxide (NO), ferric reducing antioxidant power (FRAP), and superoxide dismutase (SOD) were also measured. Expression levels of HIF-1α and its downstream genes at the protein level were assessed by Western blotting. Hydralazine showed no toxic effects on SH-SY5Y cells, at the concentration of ≤50 μmol/L. Hydralazine decreased the levels of apoptosis, malondialdehyde, and NO, and increased the activities of FRAP and SOD in cells exposed to 6-OHDA. Furthermore, hydralazine up-regulated the protein expression levels of HIF-1α, vascular endothelial growth factor, tyrosine hydroxylase, and dopamine transporter in the cells also exposed to 6-OHDA, by comparison with the cells exposed to 6-OHDA alone. In summary, hydralazine priming could attenuate the deleterious effects of 6-OHDA on SH-SY5Y cells by increasing cellular antioxidant capacity, as well as the protein levels of HIF-1α and its downstream target genes.

scholarly journals Protective Effect of Low Molecular Weight Peptides from Solenocera crassicornis Head against Cyclophosphamide-Induced Nephrotoxicity in Mice via the Keap1/Nrf2 Pathway

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 745
Author(s):  
Shuoqi Jiang ◽  
Zhuangwei Zhang ◽  
FangFang Huang ◽  
Zuisu Yang ◽  
Fangmiao Yu ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Target Genes ◽  
Inflammatory Responses ◽  
B Cell Lymphoma ◽  
Low Molecular Weight ◽  
Intragastric Administration ◽  
Related Factor ◽  
Downstream Target ◽  
Protein Levels ◽  
Total Antioxidant

The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX.

scholarly journals Distinct Posttranscriptional Mechanisms Regulate the Activity of the Zn Finger Transcription Factor Lame duck during Drosophila Myogenesis

2006 ◽  
Vol 26 (4) ◽  
pp. 1414-1423 ◽  
Author(s):  
Hong Duan ◽  
Hanh T. Nguyen
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Posttranslational Modifications ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Protein Activity ◽  
Downstream Target ◽  
Muscle Formation ◽  
Lame Duck ◽  
Fusion Competent Myoblasts

ABSTRACT Skeletal muscle formation in Drosophila melanogaster requires two types of myoblasts, muscle founders and fusion-competent myoblasts. Lame duck (Lmd), a member of the Gli superfamily of transcription factors, is essential for the specification and differentiation of fusion-competent myoblasts. We report herein that appropriate levels of active Lmd protein are attained by a combination of posttranscriptional mechanisms. We provide evidence that two different regions of the Lmd protein are critical for modulating the balance between its nuclear translocation and its retention within the cytoplasm. Activation of the Lmd protein is also tempered by posttranslational modifications of the protein that do not detectably change its subcellular localization. We further show that overexpression of Lmd protein derivatives that are constitutively nuclear or hyperactive results in severe muscle defects. These findings underscore the importance of regulated Lmd protein activity in maintaining proper activation of downstream target genes, such as Mef2, within fusion-competent myoblasts.

Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo

2010 ◽  
Vol 298 (3) ◽  
pp. E548-E554 ◽  
Author(s):  
Rickard Westergren ◽  
Daniel Nilsson ◽  
Mikael Heglind ◽  
Zahra Arani ◽  
Mats Grände ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Target Genes ◽  
Whole Body ◽  
Wild Type ◽  
Intravenous Glucose ◽  
Downstream Target ◽  
Protein Levels

Many members of the forkhead genes family of transcription factors have been implicated as important regulators of metabolism, in particular, glucose homeostasis, e.g., Foxo1, Foxa3, and Foxc2. The purpose of this study was to exploit the possibility that yet unknown members of this gene family play a role in regulating glucose tolerance in adipocytes. We identified Foxf2 in a screen for adipose-expressed forkhead genes. In vivo overexpression of Foxf2 in an adipose tissue-restricted fashion demonstrated that such mice display a significantly induced insulin secretion in response to an intravenous glucose load compared with wild-type littermates. In response to increased Foxf2 expression, insulin receptor substrate 1 (IRS1) mRNA and protein levels are significantly downregulated in adipocytes; however, the ratio of serine vs. tyrosine phosphorylation of IRS1 seems to remain unaffected. Furthermore, adipocytes overexpressing Foxf2 have a significantly lower insulin-mediated glucose uptake compared with wild-type adipocytes. These findings argue that Foxf2 is a previously unrecognized regulator of cellular and systemic whole body glucose tolerance, at least in part, due to lower levels of IRS1. Foxf2 and its downstream target genes can provide new insights with regard to identification of novel therapeutic targets.

scholarly journals Gfi1 Upregulates c-Myc Expression and Promotes c-Myc-Driven Cell Proliferation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3769-3769
Author(s):  
Yangyang Zhang ◽  
Fan Dong
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Transcriptional Repression ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Protein Levels ◽  
Enhanced Expression ◽  
Ubiquitin Proteasome

Gfi1 is a zinc-finger transcriptional repressor that plays an important role in hematopoiesis. When aberrantly activated, Gfi1 may function as a weak oncoprotein in the lymphoid system, but collaborate strongly with c-Myc in lymphomagenesis. c-Myc is a transcription factor that is frequently activated in human cancers including leukemia and lymphoma mainly due to its overexpression as a result of gene amplifications and chromosomal translocations. c-Myc overexpression may also result from stabilization of c-Myc protein, which is highly unstable and rapidly degraded through the ubiquitin-proteasome pathway. The mechanism by which Gfi1 collaborates with c-Myc in lymphomagenesis is incompletely understood. c-Myc activates gene expression by forming a heterodimeric complex with the partner protein Max, but may also repress target genes through interaction with transcription factor Miz-1. We previously showed that Gfi1 indirectly interacts with c-Myc through Miz-1 and collaborates with c-Myc to repress CDK inhibitors p21Cip1 and p15Ink4B. In this study, we show that Gfi1 augmented the level of c-Myc protein transiently expressed in Hela cells and the levels of MycER fusion protein stably expressed in the mouse pro-B Ba/F3 and myeloid 32D cells. The C-terminal ZF domains of Gfi1, but not its transcriptional repression and DNA binding activities, were required for c-Myc upregulation. Notably, although Miz-1 has been shown to stabilize c-Myc protein, the expression of c-Myc V394D mutant, which is defective in Miz-1 interaction, was still upregulated by Gfi1, suggesting that Gfi1-mediated c-Myc upregulation was independent of Miz-1 interaction. We further show that Gfi1 overexpression led to reduced polyubiquitination and increased stability of c-Myc protein. Interestingly, the levels of endogenous c-Myc mRNA and protein were augmented upon induction of Gfi1 expression in Ba/F3 and Burkitt lymphoma Ramos cells transduced with the doxycycline-inducible Gfi1 lentiviral construct, but reduced in Gfi1-knocked down human leukemic HL60 and U937 cells. Additionally, targeted deletion of Gfi1 resulted in reduced c-Myc expression in mouse lineage negative bone marrow cells, which was associated with a decline in the expression of c-Myc-activated target genes. The oncogenic potential of Myc derives from its ability to stimulate cell proliferation. Our results demonstrate that inducible expression of Gfi1 in Ba/F3 cells expressing MycER promoted Myc-driven cell cycle progression and proliferation. Thus, in addition to its role in c-Myc-mediated transcriptional repression, Gfi1 upregulates c-Myc expression at both mRNA and protein levels, leading to enhanced expression of c-Myc-activated genes and augmented cell proliferation driven by c-Myc. Together, these data may reveal a novel mechanism by which Gfi1 collaborates with c-Myc in lymphomagenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Analysis and Functional Verification of PoWRI1 Gene Associated with Oil Accumulation Process in Paeonia ostii

2021 ◽  
Vol 22 (13) ◽  
pp. 6996
Author(s):  
Jing Sun ◽  
Tian Chen ◽  
Mi Liu ◽  
Daqiu Zhao ◽  
Jun Tao
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Target Genes ◽  
De Novo ◽  
Fatty Acid Content ◽  
Functional Verification ◽  
Oil Accumulation ◽  
Reading Frame ◽  
Downstream Target ◽  
Expression Of Genes

The plant transcription factor WRINKLED1 (WRI1), a member of AP2/EREBP, is involved in the regulation of glycolysis and the expression of genes related to the de novo synthesis of fatty acids in plastids. In this study, the key regulator of seed oil synthesis and accumulation transcription factor gene PoWRI1 was identified and cloned, having a complete open reading frame of 1269 bp and encoding 422 amino acids. Subcellular localization analysis showed that PoWRI1 is located at the nucleus. After the expression vector of PoWRI1 was constructed and transformed into wild-type Arabidopsis thaliana, it was found that the overexpression of PoWRI1 increased the expression level of downstream target genes such as BCCP2, KAS1, and PKP-β1. As a result, the seeds of transgenic plants became larger, the oil content increased significantly, and the unsaturated fatty acid content increased, which provide a scientific theoretical basis for the subsequent use of genetic engineering methods to improve the fatty acid composition and content of plant seeds.

Identification of otx2 target genes and restrictions in ectodermal competence during Xenopus cement gland formation

Development ◽  
1997 ◽  
Vol 124 (2) ◽  
pp. 471-481 ◽  
Author(s):  
L.S. Gammill ◽  
H. Sive
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Homeobox Gene ◽  
Cement Gland ◽  
Inhibitory Effects ◽  
Temporal Modulation ◽  
Downstream Target ◽  
Positional Identity ◽  
Direct Target ◽  
Differentiation Marker

The homeobox gene otx2 is a key regulator of positional identity in vertebrates, however its downstream target genes and mechanism of action are not known. We have analyzed otx2 function during formation of the Xenopus cement gland, an organ that expresses otx2. The cement gland forms at early neurula from extreme anterior ectoderm and corresponds to the chin primordium of mammals. Previous studies (Blitz, I. and Cho, K. (1995) Development 121, 993–1004; Pannese, M., Polo, C., Andreazzoli, M., Vignali, R., Kablar, B., Barsacchi, G. and Boncinelli, E. (1995) Development 121, 707–720) showed that misexpressed otx2 could activate cement gland formation. However, it was not clear whether this was a direct effect of otx2 or a secondary consequence of other tissues induced by otx2. In this study we ask whether otx2 activity is spatially and temporally restricted in the ectoderm and whether cement gland-specific genes are direct targets of otx2. In order to control the timing of otx2 activity, we constructed a dexamethasone-inducible otx2 protein (otx2-GR) by fusion with the ligand-binding domain of the glucocorticoid receptor. We conclude first, that regionally restricted factors regulate otx2 activity since otx2-GR is able to activate the cement gland markers XCG and XAG only in ventrolateral ectoderm, and never in the neural plate. Second, we show that temporal responsiveness of the ectoderm to otx2-GR is limited, beginning only at mid-gastrula but continuing as late as tailbud stages. Third, we show that otx2-GR activates expression of the cement gland differentiation marker XCG in the absence of protein synthesis, identifying a direct target of otx2. otx2-GR can also activate expression of the endogenous otx2 gene, defining an autoregulatory loop. Fourth, we show that otx2-GR is sufficient to overcome the inhibitory effects of retinoic acid on cement gland formation, indicating that this effect is caused by failure to express otx2. Corroboratively, we show that otx2 autoactivation is prevented by retinoic acid. Together, these findings suggest that otx2 directly controls cement gland differentiation, and that spatial and temporal modulation of otx2 activity limits cement gland formation to the front of the embryo.

A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3221-3232 ◽  
Author(s):  
J.R. McWhirter ◽  
M. Goulding ◽  
J.A. Weiner ◽  
J. Chun ◽  
C. Murre
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Target Genes ◽  
Representational Difference Analysis ◽  
Bhlh Transcription Factor ◽  
Fibroblast Growth ◽  
Downstream Target ◽  
Developing Nervous System

Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.

ThejingZn-finger transcription factor is a mediator of cellular differentiation in theDrosophilaCNS midline and trachea

Development ◽  
2002 ◽  
Vol 129 (11) ◽  
pp. 2591-2606 ◽  
Author(s):  
Yalda Sedaghat ◽  
Wilson F. Miranda ◽  
Margaret J. Sonnenfeld
Keyword(s):  
Transcription Factor ◽  
Cellular Differentiation ◽  
Target Genes ◽  
Marker Gene ◽  
Downstream Target ◽  
Tracheal Cell ◽  
Marker Gene Expression ◽  
Embryonic Cns ◽  
Cns Midline ◽  
Drosophila Embryos

We establish that the jing zinc-finger transcription factor plays an essential role in controlling CNS midline and tracheal cell differentiation. jing transcripts and protein accumulate from stage 9 in the CNS midline, trachea and in segmental ectodermal stripes. JING protein localizes to the nuclei of CNS midline and tracheal cells implying a regulatory role during their development. Loss of jing-lacZ expression in homozygous sim mutants and induction of jing-lacZ by ectopic sim expression establish that jing is part of the CNS midline lineage. We have isolated embryonic recessive lethal jing mutations that display genetic interactions in the embryonic CNS midline and trachea, with mutations in the bHLH-PAS genes single-minded and trachealess, and their downstream target genes (slit and breathless). Loss- and gain-of-function jing is associated with defects in CNS axon and tracheal tubule patterning. In jing homozygous mutant embryos, reductions in marker gene expression and inappropriate apoptosis in the CNS midline and trachea establish that jing is essential for the proper differentiation and survival of these lineages. These results establish that jing is a key component of CNS midline and tracheal cell development. Given the similarities between JING and the vertebrate CCAAT-binding protein AEBP2, we propose that jing regulates transcriptional mechanisms in Drosophila embryos and promotes cellular differentiation in ectodermal derivatives.

scholarly journals VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

2017 ◽  
Vol 37 (13) ◽  
Author(s):  
Xianxi Wang ◽  
Anthony Arceci ◽  
Kelly Bird ◽  
Christine A. Mills ◽  
Rajarshi Choudhury ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Chromosome Instability ◽  
Vital Role ◽  
Activation Mechanism ◽  
Cycle Progression ◽  
Protein Levels ◽  
Ubiquitin System

ABSTRACT The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system.

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