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Denis C. Guttridge, Ph.D.
Associate Professor
The Ohio State University Medical Center
460 W. 12th Avenue
Biomedical Research Tower, 910
Columbus, OH 43210
Phone: (614) 688-4507
Fax: (614) 688-8675
Email: denis.guttridge@osumc.edu
Education & Training:
University of California, San Diego, 1986 B.A. in Biochemistry
and Cell Biology
California State University, Long Beach, 1988 M.A. in Biochemistry
University
of California, Irvine, 1996 Ph.D. in Biological Sciences
University of North
Carolina, Chapel Hill, 2000 Postdoctoral Fellow
Research Interest:
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.
To this point, our findings have elucidated that NF-kB acts in immature
skeletal muscle cells as an inhibitor of differentiation, and we further
identified that this activity occurs through multiple mechanisms. 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.
Selected Publications:
- 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.
- Ladner, K.J., Caligiuri, M. A., Guttridge, D. C. (2003). TNF
Induces the Biphasic Activation of NF-kB in Skeletal Muscle Leading
to Cytokine-Induced Protein Loss. J. Biol. Chem. 278: 2294-2303.
- 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.
- Dahlman, J., Wang, J., Bakkar, N., and Guttridge, D.C., (2008)
The RelA/p65 subunit of NF-kB specifically regulates cyclin D1
protein stability: Implications for cell cycle withdrawal and skeletal
myogenesis, J. Cell. Biochem., 106:42-51.
- 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, J. Biol. Chem. 285:5479-5487.
- Bakkar, N. and Guttridge, D.C., (2010), NF-kB signaling: A tale of two pathways in skeletal myogenesis, Physiol. Rev., 90: 495-511.
- 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, In Press.
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