Dataset Information

E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription.

ABSTRACT: Selective recognition of the E-box sequences on muscle gene promoters by heterodimers of myogenic basic helix-loop-helix (bHLH) transcription factors, such as MyoD, with the ubiquitous bHLH proteins E12 and E47 is a key event in skeletal myogenesis. However, homodimers of MyoD or E47 are unable of binding to and activating muscle chromatin targets, suggesting that formation of functional MyoD/E47 heterodimers is pivotal in controlling muscle transcription. Here we show that p38 MAPK, whose activity is essential for myogenesis, regulates MyoD/E47 heterodimerization. Phosphorylation of E47 at Ser140 by p38 induces MyoD/E47 association and activation of muscle-specific transcription, while the nonphosphorylatable E47 mutant Ser140Ala fails to heterodimerize with MyoD and displays impaired myogenic potential. Moreover, inhibition of p38 activity in myocytes precludes E47 phosphorylation at Ser140, which results in reduced MyoD/E47 heterodimerization and inefficient muscle differentiation, as a consequence of the impaired binding of the transcription factors to the E regulatory regions of muscle genes. These findings identify a novel pro-myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis.

SUBMITTER: Lluis F

PROVIDER: S-EPMC554117 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription.

Lluís Frederic F Ballestar Esteban E Suelves Mònica M Esteller Manel M Muñoz-Cánoves Pura P

The EMBO journal 20050217 5

Selective recognition of the E-box sequences on muscle gene promoters by heterodimers of myogenic basic helix-loop-helix (bHLH) transcription factors, such as MyoD, with the ubiquitous bHLH proteins E12 and E47 is a key event in skeletal myogenesis. However, homodimers of MyoD or E47 are unable of binding to and activating muscle chromatin targets, suggesting that formation of functional MyoD/E47 heterodimers is pivotal in controlling muscle transcription. Here we show that p38 MAPK, whose activ ...[more]

PMID: 15719023

Similar Datasets

Project description:BackgroundRenal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown.MethodsIn this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis.ResultsThe results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1.ConclusionThe findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase.

Project description:UnlabelledBackgroundThe p38 mitogen-activated protein kinases (MAPK) family plays pivotal roles in skeletal muscle metabolism. Recent evidence revealed that p38? and p38? exert paradoxical effects on muscle protein homeostasis. However, it is unknown why p38?, but not p38?, is capable of mediating muscle catabolism via selective activation of the C/EBP? that upregulates atrogin1/MAFbx.MethodsTryptic phosphopeptide mapping was carried out to identify p38?- and p38?-mediated phosphorylation sites in C/EBP?. Chromosome immunoprecipitation (ChIP) assay was used to evaluate p38? and p38? effect on C/EBP? binding to the atrogin1/MAFbx promoter. Overexpression or siRNA-mediated gene knockdown of p38? and p38?, and site-directed mutagenesis or knockout of C/EBP?, were used to analyze the roles of these kinases in muscle catabolism in C2C12 myotubes and mice.ResultsCellular expression of constitutively active p38? or p38? resulted in phosphorylation of C/EBP? at multiple serine and threonine residues; however, only p38? phosphorylated Thr-188, which had been known to be critical to the DNA-binding activity of C/EBP?. Only p38?, but not p38?, activated C/EBP?-binding to the atrogin1/MAFbx promoter. A C/EBP? mutant in which Thr-188 was replaced by alanine acted as a dominant-negative inhibitor of atrogin1/MAFbx upregulation induced by either p38? or Lewis lung carcinoma (LLC) cell-conditioned medium (LCM). In addition, knockdown of p38? specifically inhibited C/EBP? activation and atrogin1/MAFbx upregulation induced by LCM. Finally, expression of active p38? in mouse tibialis anterior specifically induced C/EBP? phosphorylation at Thr-188, atrogin1/MAFbx upregulation and muscle mass loss, which were blocked in C/EBP?-null mice.ConclusionsThe ? and ? isoforms of p38 MAPK are capable of recognizing distinct phosphorylation sites in a substrate. The unique capacity of p38? in mediating muscle catabolism is due to its capability in phosphorylating Thr-188 of C/EBP?.

Dataset Information

E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription.

Publications

E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets