A novel functional co-operation between MyoD, MEF2 and TRα1 is sufficient for the induction of GLUT4 gene transcription

Santalucı́a, Tomàs; Moreno, Horacio; Palacı́n, Manuel; Yacoub, Magdi H.; Brand, Nigel J.; Zorzano, António

doi:10.1006/jmbi.2001.5091

Cited by 70 publications

(67 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For this purpose, we used two constructs: pGL3-ratGLUT4Δ1, which includes the MEF2 binding site in the rat promoter [11,31], and pGL3-ratGLUT4Δ2, which includes the putative NF1 binding site [14]. L6 cells were transfected and luciferase activity was assayed in myotubes after the addition of insulin (100 nmol/l) or tungstate (1 mmol/l).…”

Section: Resultsmentioning

confidence: 99%

“…Design of reporter gene constructs The pGL3-ratGLUT4 construct was made by cloning a genomic DNA fragment encompassing positions −2212 to + 164 of the rat Glut4 gene from clone −2212/+147G4CAT (a gift from A. Zorzano [31]), into pGL3-Basic vector (Promega, Madison, WI, USA). pGL3-ratGLUT4Δ1 was obtained by deletion of a SmaI-BstXI fragment of pGL3-ratGLUT4, encompassing positions −502 to −243.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis The aim of this study was to investigate the action of the glucose-lowering compound sodium tungstate on glucose transport in muscle myotubes and to unravel the molecular events underlying the effects observed. Methods We studied the effects of tungstate on 2-deoxy-Dglucose uptake, levels and translocation of the glucose transporters GLUT4 and GLUT1, and Glut4 (also known as Slc2a4) promoter activity. We also measured the modifications of individual components of the signalling pathways involved in the effects observed. Results Tungstate increased 2-deoxy-D-glucose uptake in differentiated L6 myotubes through an increase in the total amount and translocation of GLUT4 transporter. The effects on glucose uptake were additive to those of insulin. Tungstate activated transcription of the Glut4 promoter, as shown by an increase in Glut4 mRNA, and by a promoter reporter assay. The assay of deletions of the Glut4 promoter indicated that the effect of tungstate is mediated by the myocyte enhancer factor 2 (MEF2)-binding domain. Accordingly, MEF2 levels and DNA binding activities were increased in response to the treatment. Tungstate-induced glucose uptake and GLUT4 transcriptional activation were dependent on the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), while no changes were observed in the phosphorylation state of the β subunit of the insulin receptor, in the phosphatidylinositol 3-kinase pathway or in the activation of 5′AMP-activated protein kinase. Conclusions/interpretation Tungstate activates glucose uptake in myotubes through a novel ERK1/2-dependent mechanism. This effect is exerted by an increase in the content and translocation of the GLUT4 transporter. This is the first report of a glucose-lowering compound activating Glut4 transcription through an ERK1/2-dependent increase in MEF2 levels.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

et al. 2008

View full text Add to dashboard Cite

show abstract

“…It is thought that PGC-1 is primarily recruited to the MEF-2 isoforms C and D (38), whereas GLUT4 expression is primarily mediated by MEF-2A (39). Although this discrepancy could suggest that PGC-1 is not functionally involved in GLUT4 expression, it has been found that MEF-2A is required to form a heterodimer with MEF-2D to drive GLUT4 expression (39,40). The function of the MEF-2A/D heterodimer has not been established, but it is possible that the role of MEF-2D is to recruit transcriptional coactivators such as PGC-1 to MEF-2A.…”

Section: Discussionmentioning

confidence: 99%

Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle

2004

View full text Add to dashboard Cite

Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action. Exercise increases GLUT4 gene and protein expression, and a binding site for the myocyte enhancer factor 2 (MEF-2) is required on the GLUT4 promoter for this response. However, the molecular mechanisms involved remain elusive. In various cell systems, MEF-2 regulation is a balance between transcriptional repression by histone deacetylases (HDACs) and transcriptional activation by the nuclear factor of activated T-cells (NFAT), peroxisome proliferator-activated receptor-␥ coactivator 1 (PGC-1), and the p38 mitogen-activated protein kinase. The purpose of this study was to determine if these same mechanisms regulate MEF-2 in contracting human skeletal muscle. Seven subjects performed 60 min of cycling at ϳ70% of Vo 2peak . After exercise, HDAC5 was dissociated from MEF-2 and exported from the nucleus, whereas nuclear PGC-1 was associated with MEF-2. Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance. This result was associated with p38 sequence-specific phosphorylation of MEF-2 and an increase in GLUT4 mRNA. Finally, we found no role for NFAT in MEF-2 regulation. From these data, it appears that HDAC5, PGC-1, and p38 regulate MEF-2 and could be potential targets for modulating GLUT4 expression.

show abstract

“…In the mesenchymal embryonic cells which do not express GLUT4, overexpression of MyoD with MEF2A and TRa1 resulted in the upregulation of GLUT4 gene. The enhancer binding site is localized to 7520 to 7420 of the GLUT4 promoter which contains respective MEF2 and TRa1 binding sites (42). Although the activating role of MyoD on the GLUT4 gene expression is clear, the mechanism explaining the synergism among MyoD, MEF2A, and TRa1 is unknown.…”

Section: Myogenic Bhlh Factors (Myod)mentioning

confidence: 99%

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

Kwon

Kim

et al. 2007

IUBMB Life

View full text Add to dashboard Cite

SummaryThe gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF-a, TR-1a, KLF15, SREBP-1c, C/EBP-a, O/E-1, free fatty acids, PAPRg, LXRa, NF-1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM.

show abstract

A novel functional co-operation between MyoD, MEF2 and TRα1 is sufficient for the induction of GLUT4 gene transcription

Cited by 70 publications

References 40 publications

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

Contact Info

Product

Resources

About