Denis C. Guttridge, PhD
Assistant Professor
Department of Molecular Virology, Immunology & Medical Genetics
554A Tzagournis Medical Research Facility
420 W 12th Ave
Columbus , OH 43210
Phone: (614) 688-3137
Fax: (614) 247-6842
denis.guttridge@osumc.edu

Research Interests
Dr. Guttridge’s laboratory studies the NF-kappa B (NF-kB) family of transcription factors and the role they play in cellular growth and differentiation. This class of transcription factors is somewhat unique in that they are predominantly localized in the cytoplasm, bound to an inhibitor protein named IkB. In response to a stimulus, IkB becomes phosphorylated and subsequently degraded, thus releasing NF-kB to freely translocate to the nucleus. This stimulus can be quite diverse ranging from inflammatory cytokines, to viral and bacterial products, and even signals engaged by oncogenes. Once in the nucleus, NF-kB binds to a specific DNA sequence and interacts with co-activators and the basal transcriptional machinery to activate gene expression.

Functionally, NF-kB is known to play a critical role in regulating the immune response. It also serves important functions in regulating apoptosis, cell growth and cellular differentiation. However, much less is known about how NF-kB functions in pathophysiological conditions such as cancer. Insight into the molecular mechanisms that underlie NF-kB regulation in transformed cells is needed to determine its potential as a chemotherapeutic target.

Our experimental approach to gaining insight on the role of NF-kB in oncogenesis has been to first study how NF-kB functions to regulate normal cell growth and differentiation. To perform this analysis, we utilize a well characterized in vitro skeletal muscle differentiation model, which involves proliferating progenitor myoblast cells undergoing growth arrest and fusing into terminally differentiated myofibers. In these cells, NF-kB functions as a negative regulator of differentiation. Mechanistically, NF-kB acts on at least two levels. First, it exhibits a growth promoting activity, which correlates with a regulatory activity in the G1 phase of the cell cycle. Second, NF-kB negatively regulates differentiation by inhibiting the expression of MyoD, a “master switch” transcription factor required for the differentiation of skeletal muscle. Our studies also reveal that activation of NF-kB in myofibers can compromise the differentiation status of these cells. This latter finding may have implications for better understanding how muscle decay occurs in a condition called cachexia, which affects a majority of cancer patients and is thought to contribute to nearly a third of all cancer deaths.

Our current research efforts are directed on the following three fronts:

1. We are determining the role of NF-kB in the early G1 phase of the cell cycle. Evidence indicates that NF-kB activity is required for quiescent cells to re-enter cell cycle through the transcriptional activation of cyclin D1. We are addressing other mechanisms by which NF-kB regulates cyclin/cdk complexes to promote cell growth.
   
   
2. We are examining the mechanism by which NF-kB regulates muscle decay, relevant to cancer-induced cachexia. To study how NF-kB activation triggers muscle damage, we are using both in vitro differentiation and animal cachexia models. Inhibitor drugs of NF-kB activity are being utilized to test the requirement of NF-kB in muscle decay in both models.
   
   
3. We are conducting studies to address the regulatory mechanism of NF-kB on MyoD expression. Evidence indicates that inhibition of MyoD by NF-kB occurs at the post-transcriptional level. We are determining the region of the MyoD mRNA that is susceptible to NF-kB regulation, and the trans-acting factors that mediate the effects of NF-kB on MyoD mRNA expression.

Education & Training
University of California, San Diego, 1986 B.A. in Biochemistry and Cell Biology

California State University, Long Beach, 1988 M.S. in Biochemistry

University of California, Irvine 1996 Ph.D. Biological Sciences

1996-2001 Postdoctoral Research, University of North Carolina, Chapel Hill The Role of NF-kB in Cell Growth and Differentiation

Select Publications
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

Cogswell PC, Kashatus DF, Keifer JA, Guttridge DC, Reuther JY, Bristow C, Roy S, Nicholson DW, Baldwin AS. (2003) NF-kappa B and Ikappa Balpha are found in the mitochondria: Evidence for regulation of mitochondrial gene expression by NF-kappa B. J Biol Chem. 278: 2963-2968

Keifer JA, Guttridge D. C., Ashburner BP, Baldwin AS Jr. (2001) Inhibition of NF-kappa B Activity by Thalidomide through Suppression of Ikappa B Kinase Activity. J Biol Chem. 276: 22382-22387

Chen S, Guttridge D. C., You Z, Zhang Z, Fribley A, Mayo MW, Kitajewski J, Wang CY. (2001) Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J Cell Biol. 152: 87-96

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

Madrid, L.V., Wang, C. Y., Guttridge, D. C., Schottelius, A. J. G., Baldwin, A. S. Jr., and Mayo, M. W., (2000) Akt Suppresses Apoptosis by Stimulating the Transactivation Potential of the RelA/p65 Subunit of NF-kB. Mol. Cell. Biol. 20: 1626-1638

Cogswell, P. C., Guttridge, D. C., Funkhouser, W. K., and Baldwin, A. S., Jr. (2000) Selective Activation of NF-kB Subunits in Human Breast Cancer: Potential Roles for NF-kB2/p52 and for Bcl-3. Oncogene, 19(9):1123-1131

Guttridge, D. C., Albanese, C., Reuther, J. Y., Pestell, R.G., and Baldwin, A.S. Jr. (1999) NF-kappaB Controls Cell Growth and Differentiation Through Transcriptional Regulation of Cyclin D1. Mol. Cell. Biol. 19: 5785-5799

Wang C.Y., Guttridge, D. C., Mayo, M.W., and Baldwin, A.S. Jr. (1999) NF-KappaB Induces Expression of the Bcl-2 Homologue A1/Bfl-1 to Preferentially Suppress Chemotherapy-Induced Apoptosis. Mol. Cell. Biol. 19: 5923-5929

Batra, R. K., Guttridge, D. C., Brenner, D. A., Dubinett, S. M., Baldwin, A. S., and Boucher, R. C. (1999). Ikappa B alpha Gene Transfer is Cytotoxic to Squamous-Cell Cancer Cells and Sensitizes Them to Tumor Necrosis Factor-Alpha-Mediated Cell Death. Amer. J. Res. Cell. Mol. Biol. 21: 238-245