title: Protein-DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice.
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-kappaB), 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, PPARalpha, 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.
authors.affiliation: Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veteren Affairs Medical Center, Loma Linda, CA 92357, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Dogra
authors.forename: Daya Shankar
authors.initials: DS
authors.lastname: Srivastava
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D040081:Protein Array Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016189:Dystrophin; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53