scholarly journals AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

2011 ◽  
Vol 286 (18) ◽  
pp. 16426-16434 ◽  
Author(s):  
Jun-Xing Zhao ◽  
Wan-Fu Yue ◽  
Mei-Jun Zhu ◽  
Min Du
Keyword(s):  
Cell Differentiation ◽  
Protein Kinase ◽  
Mrna Expression ◽  
Histone Deacetylase ◽  
Myocyte Enhancer Factor 2 ◽  
Myocyte Enhancer Factor ◽  
Ampk Activity ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase ◽  
Enhancer Factor

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering β-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with β-catenin content. Chemical inhibition of HDAC5 increased β-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular β-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate β-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on β-catenin expression. In conclusion, AMPK promotes β-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the β-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/β-catenin signaling pathway.

Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase

2001 ◽  
Vol 91 (3) ◽  
pp. 1073-1083 ◽  
Author(s):  
Donghai Zheng ◽  
Paul S. MacLean ◽  
Steven C. Pohnert ◽  
John B. Knight ◽  
Ann Louise Olson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Consensus Sequence ◽  
Proximal Promoter ◽  
Response To Treatment ◽  
Mrna Levels ◽  
Myocyte Enhancer Factor 2 ◽  
Glut 4 ◽  
Myocyte Enhancer Factor ◽  
Amp Activated Protein Kinase ◽  
Enhancer Factor

Skeletal muscle GLUT-4 transcription in response to treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a known activator of AMP-activated protein kinase (AMPK), was studied in rats and mice. The increase in GLUT-4 mRNA levels in response to a single subcutaneous injection of AICAR, peaked at 13 h in white and red quadriceps muscles but not in the soleus muscle. The mRNA level of chloramphenicol acyltransferase reporter gene which is driven by 1,154 or 895 bp of the human GLUT-4 proximal promoter was increased in AICAR-treated transgenic mice, demonstrating the transcriptional upregulation of the GLUT-4 gene by AICAR. However, this induction of transcription was not apparent with 730 bp of the promoter. In addition, nuclear extracts from AICAR-treated mice bound to the consensus sequence of myocyte enhancer factor-2 (from −473 to −464) to a greater extent than from saline-injected mice. Thus AMP-activated protein kinase activation by AICAR increases GLUT-4 transcription by a mechanism that requires response elements within 895 bp of human GLUT-4 proximal promoter and that may be cooperatively mediated by myocyte enhancer factor-2.

Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase

2005 ◽  
Vol 289 (6) ◽  
pp. E1071-E1076 ◽  
Author(s):  
Burton F. Holmes ◽  
David P. Sparling ◽  
Ann Louise Olson ◽  
William W. Winder ◽  
G. Lynis Dohm
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transporter ◽  
Myocyte Enhancer Factor 2 ◽  
Consensus Sequences ◽  
Glut4 Expression ◽  
Myocyte Enhancer Factor ◽  
Amp Activated Protein Kinase ◽  
Enhancer Factor

As the primary glucose transporter in skeletal muscle, GLUT4 is an important factor in the regulation of blood glucose. We previously reported that stimulation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) increased GLUT4 expression in muscle. GLUT4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) have been shown to be important for normal GLUT4 expression because deletion or truncation of the consensus sequences on the promoter causes depressed GLUT4 mRNA expression. This led to the current study to investigate possible roles for GEF and MEF2 in mediating the activation of GLUT4 gene transcription in response to AMPK. Here we show that, although AMPK does not appear to phosphorylate MEF2A, AMPK directly phosphorylates the GEF protein in vitro. MEF2 and GEF are activated in response to AMPK as we observed translocation of both to the nucleus after AICAR treatment. Nuclear MEF2 protein content was increased after 2 h, and GEF protein was increased in the nucleus 1 and 2 h post-AICAR treatment. Last, GEF and MEF2 increase in binding to the GLUT4 promoter within 2 h after AICAR treatment. Thus we conclude that GEF and MEF2 mediate the AMPK-induced increase in transcription of skeletal muscle GLUT4. AMPK can phosphorylate GEF and in response to AICAR, GEF, and MEF2 translocate to the nucleus and have increased binding to the GLUT4 promoter.

scholarly journals AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5

2013 ◽  
Vol 305 (8) ◽  
pp. C887-C895 ◽  
Author(s):  
Xing Fu ◽  
Jun-Xing Zhao ◽  
Junfang Liang ◽  
Mei-Jun Zhu ◽  
Marc Foretz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Muscle Development ◽  
C2c12 Cells ◽  
Luciferase Assay ◽  
Global Epidemic ◽  
Primary Myoblasts ◽  
Ampk Activity ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

There is a global epidemic of obesity, and obesity is known to inhibit AMP-activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPKα1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPKα1 knockout mice, we further demonstrate that AMPKα1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPKα1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPKα1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated.

scholarly journals Direct Interaction of Ca2+/Calmodulin Inhibits Histone Deacetylase 5 Repressor Core Binding to Myocyte Enhancer Factor 2

2003 ◽  
Vol 278 (20) ◽  
pp. 17625-17635 ◽  
Author(s):  
Imre Berger ◽  
Christoph Bieniossek ◽  
Christiane Schaffitzel ◽  
Markus Hassler ◽  
Eugenio Santelli ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Direct Interaction ◽  
Myocyte Enhancer Factor 2 ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

AMP-activated protein kinase and the regulation of glucose transport

2006 ◽  
Vol 291 (5) ◽  
pp. E867-E877 ◽  
Author(s):  
Nobuharu Fujii ◽  
Niels Jessen ◽  
Laurie J. Goodyear
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Cardiac Muscle ◽  
Glucose Transport ◽  
Whole Body ◽  
Insulin Resistant ◽  
Treatment And Prevention ◽  
Ampk Activity ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by acute increases in the cellular [AMP]/[ATP] ratio. In skeletal and/or cardiac muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress. There are many lines of evidence that increasing AMPK activity in skeletal muscle results in increased rates of glucose transport. Although similar to the effects of insulin to increase glucose transport in muscle, it is clear that the underlying mechanisms for AMPK-mediated glucose transport involve proximal signals that are distinct from that of insulin. Here, we discuss the evidence for AMPK regulation of glucose transport in skeletal and cardiac muscle and describe research investigating putative signaling mechanisms mediating this effect. We also discuss evidence that AMPK may play a role in enhancing muscle and whole body insulin sensitivity for glucose transport under conditions such as exercise, as well as the use of the AMPK activator AICAR to reverse insulin-resistant conditions. The identification of AMPK as a novel glucose transport mediator in skeletal muscle is providing important insights for the treatment and prevention of type 2 diabetes.

scholarly journals Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2

2006 ◽  
Vol 27 (4) ◽  
pp. 1280-1295 ◽  
Author(s):  
Serge Grégoire ◽  
Lin Xiao ◽  
Jianyun Nie ◽  
Xiaohong Zhang ◽  
Minghong Xu ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Thyroid Hormone Receptor ◽  
Trichostatin A ◽  
Hek293 Cells ◽  
Physical Interaction ◽  
Myocyte Enhancer Factor 2 ◽  
Specific Domain ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

ABSTRACT The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.

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