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A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.

Publication ,  Journal Article
Choi, M-C; Cohen, TJ; Barrientos, T; Wang, B; Li, M; Simmons, BJ; Yang, JS; Cox, GA; Zhao, Y; Yao, T-P
Published in: Mol Cell
July 13, 2012

Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades.

Duke Scholars

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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

July 13, 2012

Volume

47

Issue

1

Start / End Page

122 / 132

Location

United States

Related Subject Headings

  • Transcription Factor AP-1
  • RNA Interference
  • Protein Binding
  • Phosphorylation
  • Muscular Atrophy
  • Muscle, Skeletal
  • Muscle Denervation
  • Molecular Sequence Data
  • Mice, Transgenic
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
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Choi, M.-C., Cohen, T. J., Barrientos, T., Wang, B., Li, M., Simmons, B. J., … Yao, T.-P. (2012). A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell, 47(1), 122–132. https://doi.org/10.1016/j.molcel.2012.04.025
Choi, Moon-Chang, Todd J. Cohen, Tomasa Barrientos, Bin Wang, Ming Li, Bryan J. Simmons, Jeong Soo Yang, Gregory A. Cox, Yingming Zhao, and Tso-Pang Yao. “A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.Mol Cell 47, no. 1 (July 13, 2012): 122–32. https://doi.org/10.1016/j.molcel.2012.04.025.
Choi M-C, Cohen TJ, Barrientos T, Wang B, Li M, Simmons BJ, et al. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell. 2012 Jul 13;47(1):122–32.
Choi, Moon-Chang, et al. “A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.Mol Cell, vol. 47, no. 1, July 2012, pp. 122–32. Pubmed, doi:10.1016/j.molcel.2012.04.025.
Choi M-C, Cohen TJ, Barrientos T, Wang B, Li M, Simmons BJ, Yang JS, Cox GA, Zhao Y, Yao T-P. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell. 2012 Jul 13;47(1):122–132.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

July 13, 2012

Volume

47

Issue

1

Start / End Page

122 / 132

Location

United States

Related Subject Headings

  • Transcription Factor AP-1
  • RNA Interference
  • Protein Binding
  • Phosphorylation
  • Muscular Atrophy
  • Muscle, Skeletal
  • Muscle Denervation
  • Molecular Sequence Data
  • Mice, Transgenic
  • Mice, Inbred C57BL