Denis C. Guttridge, PhD
Associate Professor, Ohio State University
Our laboratory studies the NF-kB family of transcription factors and the role they play in cell growth and differentiation. Aside from NF-kB’s more recognizable role in regulating immune response, strong evidence suggests that the NF-kB signaling pathway is also involved in tumor progression. However, exactly how NF-kB functions in cellular transformation has not been resolved. To further understand this disease property of NF-kB, my laboratory is using skeletal muscle as a model of cellular growth and differentiation. Skeletal muscle maturation involves growth arrest and fusion of progenitor myoblasts into terminally differentiated myofibers. These cells also have the tremendous capacity to undergo regeneration in response to injury. Under those conditions, NF-kB is activated and contributes to muscle repair by inhibiting the differentiation program. This function is most likely required to insure that myoblasts do not undergo premature differentiation. Our group has also expanded studies using in vivo models of muscle regeneration, where results support the notion that NF-kB functions in skeletal muscle to limit it’s regenerative potential. We believe this function of NF-kB may be relevant in muscle diseases such as Duchenne muscular dystrophy and cancer conditions including cachexia and rhabdomyosarcoma. The long-term goal is to not only better dissect the function and mechanisms by which NF-kB regulates muscle differentiation associated with muscle disorders, but to also determine whether NF-kB can be targeted therapeutically for the treatment of these diseases.
Skeletal muscle differentiation
Skeletal muscle disorders
Guttridge, D. C., Mayo, M. W., Madrid, L. V., Wang, C. Y., and Baldwin, A. B. Jr. (2000) NF-kB-Induced Loss of MyoD messenger RNA: Possible Role in Muscle Decay and Cachexia. Science, 289: 2363-2366.
Acharyya S., Ladner K. J., Nelsen L. L., Damrauer J., Reiser P. J., Swoap S., and Guttridge, D. C. (2004) Cancer Cachexia is Regulated by Selective Targeting of Skeletal Muscle Gene Products, J. Clin. Invest., 114: 370-378.
Acharyya S., Butchbach M.E.R., Sahenk, Z., Wang, H., Saji, M., Carathers, M., Ringel, M.D., Skipworth, R.J.E., Fearon, K.C.H., Hollingsworth, M.A., Muscarella, P., Burghes, A.H.M., Rafael-Fortney, J.A., and Guttridge, D. C. (2005) Dystrophin Glycoprotein Complex Dysfunction: A Regulatory Link Between Muscular Dystrophy and Cancer Cachexia,Cancer Cell, 8: 421-432.
Acharyya, S., Villalta, S. A., Bakkar, N., Bupha-Intr, T., Janssen, P. M., Carathers, M., Li, Z-W., Beg, A., Ghosh, S., Sahenk, Z., Weinstein, M., Gardner, K. L., Rafael-Fortney, J. A., Karin, M., Tidball, J. G., Baldwin, S. A., and Guttridge, D. C. (2007) IKK/NF-kB signaling interplay in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy, J. Clin. Invest, 117: 889-901.
Wang, H., Hertlein, E., Bakkar, N., Sun, H., Acharyya, S., Wang, J., Carathers, M., Davuluri, R. and Guttridge, D. C., (2007) NF-kB inhibits skeletal myogenesis through regulation of YY1 and transcriptional silencing of myofibrillar genes. Mol. Cell. Biol., 27: 4374-4387.
Bakkar, N., Wang, J., Ladner, K., Wang, H., Dahlman, J., Carathers, M., Acharyya, S., Rudnicki, M. A., Hollenbach, A. D., and Guttridge, D. C., (2008) IKK/NF-kB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis, J. Cell. Biol.,180: 787-802.
Wang, H., Garzon, R., Sun, H.,Ladner, K. L., Singh, R.,, Cheng, A.,, Hall, B., Qualman, S. J., Chandler, D., Croce, C., and Guttridge, D.C., (2008) NF-kB-YY1-miR-29 Regulatory Circuitry in Skeletal Myogenesis and Rhabdomyosarcoma, Cancer Cell, 14:369-381.
Wang, J., Naduparambil, K. J., Ladner, K. J., Beg, A. A., Perko, J. D., Tanner, S. M., Liyanarachchi, S., Fishel, R., and Guttridge, D. C., (2009) RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair. EMBO Rep. 10: 1272-1278.
Dahlman, J., Bakkar, N., He, W., and Guttridge, D.C., (2010), NF-kB functions in stromal fibroblasts to regulate early postnatal muscle development, J. Biol. Chem. 285:5479-5487.
Acharyya, S., Sharma, S. M. Cheng, A.S., Ladner, K.J., He, W., Kline, W., Wang, H., Ostrowski, M., Huang, T. H., Guttridge, D.C. (2010) TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: Implications in Duchenne muscular dystrophy, PLoS One, 5(8):e12479.
Bakkar, N., Ladner, K., Canan, B. D., Liyanarachchi, S., Bal, N.C., Pant, M., Periasamy, M., Li, Q., Janssen, P.M.L, and Guttridge, D. C., (2012), IKKa and Alternative NF-kB Regulate PGC-1b to Promote Oxidative Muscle Metabolism, J. Cell Biol. In Press.