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Protein–DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice

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Abstract

Inactivation of dystrophin gene is the primary cause of Duchenne muscular dystrophy (DMD) in humans and mdx mice. However, the underpinning mechanisms, which govern the pathogenesis of dystrophin-deficient skeletal muscle, remain poorly understood. We have previously reported activation of mitogen-activated protein kinases (MAPK), nuclear factor-kappa B (NF-κB), and phosphatidyl-inositol 3-kinase/Akt (PI3K/Akt) signaling pathways in diaphragm muscle of mdx mice. In this study, using a protein–DNA array-based approach, we have investigated the activation of 345 transcription factors in diaphragm muscle of 6-week old normal and dystrophin-deficient mdx mice. Our data demonstrate increased activation of a number nuclear transcription factors including AP1, HFH-3, PPARα, c.myb BP, ETF, Fra-1/JUN, kBF-A, N-rasBP, lactoferrin BP, Myb(2), EBP40_45, EKLF(1), p53(2), TFEB, Myc-Max; c-Rel; E2, ISRE; NF-kB; Stat1 p84/p91, Antioxidant RE, EVI-1, Stat3, AP3, p53, Stat4, AP4, HFH-1, FAST-1, Pax-5, and Beta-RE in the diaphragm muscle of mdx mice compared to corresponding normal mice. The level of activation for p53 was highest among all the transcription factors studied. Furthermore, higher activation of p53 in diaphragm muscle of mdx mice was associated with its increased phosphorylation and nuclear translocation. Collectively, our data suggest that the primary deficiency of dystrophin leads to the aberrant activation of nuclear transcription factors which might further contribute to muscle pathogenesis in mdx mice.

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Abbreviations

AP-1:

Activator protein-1

DMD:

Duchenne muscular dystrophy

EMSA:

Electrophoretic mobility shift assay

NF-κB:

Nuclear factor-kappa B

PI3K:

Phosphatidyl-inositol 3-kinase

STAT:

Signal transduction and activator of transcription

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Acknowledgements

This study was supported by funding from the Muscular Dystrophy Association and National Institute of Health (RO1 AG029623) to AK.

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Authors and Affiliations

  1. Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veteren Affairs Medical Center, Loma Linda, CA, 92357, USA

    Charu Dogra & Ashok Kumar

  2. Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Daya Shankar Srivastava & Ashok Kumar

Authors
  1. Charu Dogra
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  2. Daya Shankar Srivastava
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  3. Ashok Kumar
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Correspondence to Ashok Kumar.

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Dogra, C., Srivastava, D.S. & Kumar, A. Protein–DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice. Mol Cell Biochem 312, 17–24 (2008). https://doi.org/10.1007/s11010-008-9716-6

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  • DOI: https://doi.org/10.1007/s11010-008-9716-6

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