Catharine Smith, PhD
My research is focused on epigenetic mechanisms of gene expression, particularly their regulation through signaling pathways and their modulation by anti-cancer drugs. Epigenetic mechanisms play a very important role in transcriptional regulation of genes but the specifics of these mechanisms require ongoing study. Many studies focus on the role of post-translational modification of histone proteins, such as acetylation, methylation, and phosphorylation. My view is that this is only part of the full picture. Non-histone proteins that associate with chromatin can also be post-translationally modified. Without knowledge of how modifed histones and non-histone proteins work together to achieve regulation of gene expression we will not have a comprehensive understanding of epigenetic mechanisms of gene regulation. Currently we are focused on acetylation of transcriptional regulatory proteins. Proteomic studies have identified almost 2000 non-histone proteins that are modifed by acetylation in different cellular compartments yet only a small fraction of these proteins have been studied to determine how the acetylation impacts their function. We currently have two active projects that focus on the role of acetylation in signaling to chromatin.
Steroid receptors are ligand-activated transcription factors that serve to regulate many important physiological processes. Glucocorticoids regulate metabolism, immune function, stress and anxiety responses, and are important for lung development. They bind to the glucocorticoid receptor (GR) and activate it to bind to specific DNA sequences in target genes. The GR is known to associate with lysine acetyltransferases, which acetylate proteins and help the GR regulate transcription. Our work has also revealed an important role for lysine deacetylases (KDACs) in the activation of transcription by GR. This is surprising since KDACs are often cast as repressive to transcription because they remove histone acetylation. Our current goals for this project are to understand how KDACs cooperate with GR in the activation of target genes, identify which KDACs are involved (there are 11 possible candidates), and determine which proteins they deacetylate to facilitate transcription at GR target genes.
The second project is focused on the role of KDACs in growth and survival signaling in Non-Hodgkin's Lymphoma (NHL). Over the last 20 years, drugs which target KDACs have been developed, resulting in recent FDA approvals for treatment of a rare form of NHL, cutaneous T cell lymphoma. We have chosen to focus our efforts on the most common form of NHL, diffuse large B cell lymphoma (DLBCL). This is an agressive lymphoma that must be treated. The current treatment strategy is highly efficient initially, but about 50% of patients relapse within 5 years. Thus, new drugs like KDAC inhibitors are needed to either prolong remission or effectively treat relapsed DLBCL. Our goal is to understand how KDAC-inhibiting drugs impact growth in survival signaling in this cancer. Through these studies we have developed cell-based models of sensitivity and resistance to these drugs in DLBCL. We are focused on understanding the mechanisms behind sensitivity and resistance in an effort to identify biomarkers that predict response to these drugs and to find other therapeutics that might synergize with KDAC inhibitors to kill resistant DLBCL cells.
BA, Colgate University, 1983, Molecular Biology
PhD, University of Vermont, 1988, Biochemistry
Smith, C.L., Archer, T.K., Hamlin-Green, G., and Hager, G.L. (1993) Newly_expressed progesterone receptor cannot activate stable, replicated MMTV templates but acquires transactivation potential upon continuous expression. Proc. Nat. Acad. Sci. USA. 90: 11202-11206.
Pennie, W.D., Hager, G.L., and Smith, C.L. (1995) Nucleoprotein structure influences the response of the mouse mammary tumor virus promoter to activation of the cAMP signaling pathway. Mol. Cell. Biol. 15: 2125-2134.
Smith, C.L., Htun, H., Wolford, R.G., and Hager, G.L. (1997) Differential activity of progesterone and glucocorticoid receptors on MMTV templates differing in chromatin structure. J. Biol. Chem. 272: 14227-14235.
Smith, C.L., and Hager, G.L. (1997) Transcriptional Regulation of Mammalian Genes in vivo: A Tale of Two Templates. J. Biol. Chem. 272: 27493-27496.
Sheldon, L.A., Smith, C.L., Bodwell, J.E., Munck, A.U., and Hager, G.L. (1999) A Ligand Binding Domain Mutation in the Mouse GR Functionally Links Chromatin Remodeling and Transcription Initiation., Mol. Cell Biol. 19: 8146-8157.
Smith, C.L., Wolford, R.G., O’Neill, T.B., and Hager, G.L. (2000) Characterization of Transiently and Constitutively Expressed Progesterone Receptors: Evidence for Two Functional States. Mol. Endo. 14: 956-971.
List, H.J., Smith, C.L., Martinez, E., Harris, V., Danielsen, M., and Riegel, A.T. (2000) Effects of Anti-androgens on Chromatin Remodeling and Transcription of the Integrated Mouse Mammary Tumor Virus Promoter. Exp. Cell Res. 260: 160_165.
Sheldon, L.A., Becker, M., and Smith, C.L. (2001) Steroid Receptor -Mediated Histone Deacetylation and Transcription at the Mouse Mammary Tumor Virus Promoter, J. Biol. Chem. 276: 32423-32426.
Soeth, E., Thurber, D.B. and Smith C.L. (2002) The Viral Transactivator E1A Regulates the MMTV Promoter in an Isoform- and Chromatin-specific Manner, J. Biol. Chem. 277: 19847-19854.
Keeton, E.K., Fletcher, T.M., Baumann, C.T., Hager, G.L., and Smith, C.L. (2002) Glucocorticoid Receptor Domain Requirements for Chromatin Remodeling and Transcriptional Activation of the MMTV Promoter in Different Nucleoprotein Contexts. J. Biol. Chem. 277: 28247-28255.
Mulholland, N.M., Snyder, S.K., Kolla, S.S., and Smith, C.L. (2003) Chromatin-Dependent Regulation of the MMTV Promoter by cAMP signaling is Mediated Through Distinct Pathways, Exp. Cell Res. 287: 361-373.
Mullholland, N.M., Soeth, E. and Smith, C.L. (2003) Inhibition of MMTV Transcription by HDAC Inhibitors Occurs Independently of Changes in Chromatin Remodeling and is Associated with Histone Deacetylation. Oncogene 22: 4807-4818.
Botos, J.J., Xian, W., Smith, D.F. and Smith C.L. (2004) Progesterone Receptor Deficient in Chromatin Binding has an Altered Cellular State, J. Biol. Chem. 279: 15231-15239.