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

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.

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Transcription factor EB and TFE3: new metabolic coordinators mediating adaptive responses to exercise in skeletal muscle?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00339.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. E763-E768 ◽

Cited By ~ 1

Author(s):

Greg Robert Markby ◽

Kei Sakamoto

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Spatial Organization ◽

Target Genes ◽

Nuclear Translocation ◽

Contractile Activity ◽

Metabolic Reprogramming ◽

Peroxisome Proliferator ◽

Adaptive Responses ◽

Transcription Factor Eb

In response to the increased energy demands of contractions, skeletal muscle adapts remarkably well through acutely regulating metabolic pathways to maintain energy balance and in the longer term by regulating metabolic reprogramming, such as remodeling and expanding the mitochondrial network. This long-term adaptive response involves modulation of gene expression at least partly through the regulation of specific transcription factors and transcriptional coactivators. The AMPK-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) pathway has long been known to orchestrate contraction-mediated adaptive responses, although AMPK- and PGC1α-independent pathways have also been proposed. Transcription factor EB (TFEB) and TFE3, known as important regulators of lysosomal biogenesis and autophagic processes, have emerged as new metabolic coordinators. The activity of TFEB/TFE3 is regulated through posttranslational modifications (i.e., phosphorylation) and spatial organization. Under nutrient and energy stress, TFEB and TFE3 are dephosphorylated and translocate to the nucleus, where they activate transcription of their target genes. It has recently been reported that exercise promotes nuclear translocation and activation of TFEB/TFE3 in mouse skeletal muscle through the Ca2+-stimulated protein phosphatase calcineurin. Skeletal muscle-specific ablation of TFEB exhibits impaired glucose homeostasis and mitochondrial biogenesis with reduced metabolic flexibility during exercise, and global TFE3 depletion results in diminished endurance and abolished exercise-induced metabolic benefits. Transcriptomic analysis of the muscle-specific TFEB-null mice has demonstrated that TFEB regulates the expression of genes involved in glucose metabolism and mitochondrial homeostasis. This review aims to summarize and discuss emerging roles for TFEB/TFE3 in metabolic and adaptive responses to exercise and contractile activity in skeletal muscle.

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Strigolactone GR24 upregulates Nrf2 target genes and may protect against oxidative stress in skeletal muscle

F1000Research ◽

10.12688/f1000research.16172.1 ◽

2018 ◽

Vol 7 ◽

pp. 1459

Author(s):

Shalem Raju Modi ◽

Tarja Kokkola

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Skeletal Muscle ◽

Transcription Factor ◽

Stress Responses ◽

Mycorrhizal Fungi ◽

Target Genes ◽

Redox Homeostasis ◽

Antioxidant Defences ◽

Microarray Gene Expression

GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microarray gene expression profiling. GR24 upregulated the cytoprotective transcription factor Nrf2 and its target genes, activating antioxidant defences, suggesting that GR24 may protect skeletal muscle from the toxic effects of oxidative stress.

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Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation

mBio ◽

10.1128/mbio.02591-19 ◽

2019 ◽

Vol 10 (6) ◽

Author(s):

Yan-Heng Zhou ◽

Li Sun ◽

Jun Chen ◽

Wei-Wei Sun ◽

Li Ma ◽

...

Keyword(s):

Transcription Factor ◽

Aryl Hydrocarbon Receptor ◽

Metabolic Pathways ◽

Nuclear Translocation ◽

Underlying Mechanism ◽

Hiv Pathogenesis ◽

Downstream Target ◽

Potential Target ◽

Aryl Hydrocarbon ◽

Hiv 1

ABSTRACT Multiple cellular metabolic pathways are altered by HIV-1 infection, with an impact on immune activation, inflammation, and acquisition of non-AIDS comorbid diseases. The dysfunction of tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the underlying mechanism remains unknown. In this study, we demonstrated that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is activated by Trp metabolites to promote HIV-1 infection and reactivation. AHR directly binds to the HIV-1 5′ long terminal repeat (5′-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5′-LTR; moreover, the binding of AHR with HIV-1 Tat facilitates the recruitment of positive transcription factors to viral promoters. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection. IMPORTANCE Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22136996 ◽

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.

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

Development ◽

10.1242/dev.124.17.3221 ◽

1997 ◽

Vol 124 (17) ◽

pp. 3221-3232 ◽

Cited By ~ 10

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.

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

Development ◽

10.1242/dev.129.11.2591 ◽

2002 ◽

Vol 129 (11) ◽

pp. 2591-2606 ◽

Cited By ~ 3

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.

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Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor1This article is part of a Special Issue entitled Lactoferrin and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o11-070 ◽

2012 ◽

Vol 90 (3) ◽

pp. 307-319 ◽

Cited By ~ 18

Author(s):

Christophe Mariller ◽

Stephan Hardivillé ◽

Esthelle Hoedt ◽

Isabelle Huvent ◽

Socorro Pina-Canseco ◽

...

Keyword(s):

Transcription Factor ◽

Posttranslational Modifications ◽

Transcriptional Activity ◽

Target Genes ◽

Peer Review Process ◽

Good Prognosis ◽

Cycle Arrest ◽

Fine Regulation ◽

Tissue Marker

Delta-lactoferrin (ΔLf) is a transcription factor of which the expression is downregulated in cancer. It is a healthy tissue marker and a high expression level of its transcripts was correlated with a good prognosis in breast cancer. ΔLf results from alternative promoter usage of the hLf gene leading to the production of 2 isoforms with alternative N-termini: lactoferrin, which is secreted, and ΔLf, its nucleocytoplasmic counterpart. ΔLf possesses antiproliferative properties and induces cell cycle arrest. It is an efficient transcription factor interacting in vivo via a ΔLf response element found in the Skp1, Bax, DcpS, and SelH promoters. Since ΔLf possesses different target genes, modifications in its activity or concentration may have crucial effects on cell homeostasis. Posttranslational modifications modulate ΔLf transcription factor activity. Our earlier investigations showed that O-GlcNAcylation negatively regulates ΔLf transcriptional activity, whilst inhibiting its ubiquitination and increasing its half-life. On the other hand, phosphorylation potentiates ΔLf transcriptional activity. Recently, we showed that ΔLf is also modified by SUMOylation. Therefore, cooperation and (or) competition among SUMOylation, ubiquitination, phosphorylation, and O-GlcNAcylation may contribute to the establishment of a fine regulation of ΔLf transcriptional activity depending on the type of target gene and cellular homeostasis.

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MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00097.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. E1419-E1427 ◽

Cited By ~ 82

Author(s):

Hirotaka Yamamoto ◽

Katsutaro Morino ◽

Yoshihiko Nishio ◽

Satoshi Ugi ◽

Takeshi Yoshizaki ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Mitochondrial Biogenesis ◽

Target Genes ◽

Myogenic Differentiation ◽

Muscle Adaptation ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Forkhead Box ◽

Mitochondrial Transcription Factor A

MicroRNAs (miRNAs) are important posttranscriptional regulators of various biological pathways. In this study, we focused on the role of miRNAs during mitochondrial biogenesis in skeletal muscle. The expression of miR-494 was markedly decreased in murine myoblast C2C12 cells during myogenic differentiation, accompanied by an increase in mtDNA. Furthermore, the expression of predicted target genes for miR-494, including mitochondrial transcription factor A (mtTFA) and Forkhead box j3 (Foxj3), was posttranscriptionally increased during myogenic differentiation. Knockdown of miR-494 resulted in increased mitochondrial content and upregulation of mtTFA and Foxj3 at the protein level. A 3′-untranslated region reporter assay revealed that miR-494 knockdown directly upregulated the luciferase activity of mtTFA and Foxj3. All of these observations were reversed by overexpression of miR-494. Furthermore, the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.

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MondoA deficiency enhances sprint performance in mice

Biochemical Journal ◽

10.1042/bj20140530 ◽

2014 ◽

Vol 464 (1) ◽

pp. 35-48 ◽

Cited By ~ 6

Author(s):

Minako Imamura ◽

Benny Hung-Junn Chang ◽

Motoyuki Kohjima ◽

Ming Li ◽

Byounghoon Hwang ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Glucose Metabolism ◽

Endurance Exercise ◽

Target Genes ◽

Sprint Performance ◽

Response Elements ◽

Putative Target

MondoA, a transcription factor that binds to carbohydrate-response elements of putative target genes involved in glucose metabolism, is expressed predominantly in skeletal muscle. We show that MondoA-knockout (KO) mice display enhanced capacity for glycolysis and sprinting, but not for endurance exercise.

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