Catharine L Smith, PhD
Associate Professor
Department:
Pharmacology and Toxicology
(520) 626-8349
E-mail:
Location:
Pharmacy 136
Bio / Research:
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. A very exciting new area of research focuses on how these mechanisms are disrupted during tumorigenesis but may also be harnessed to treat cancer.
Signaling pathways control the expression of key genes in non-cancerous cells but are often misregulated during the process of oncogenesis. Chromatin proteins and transcription factors that interact with chromatin are often targets of these pathways. Two projects in the lab are directed at the interface of signaling pathways and chromatin. First, we are interested in the mechanism by which the female reproductive steroid, progesterone, regulates target genes in the physiological context of chromatin. Chronic progestin exposure has been linked to increased incidence of breast cancer in post-menopausal women on hormone-replacement therapy. However, the function of the progesterone receptor in mammary tissue and its role in oncogenesis are not well understood. Our current studies in this area are directed at the role of chaperone proteins in determining how the progesterone receptor functions at target genes in chromatin and how it is impacted by other signaling pathways. Second, we have discovered a novel cAMP signaling pathway that regulates cell cycle progression and are focused on identifying specific components and targets of this pathway.
Third, histone deacetylases (HDACs) are key transcriptional regulatory proteins. Inhibitors that target these enzymes have shown great promise as anti-cancer drugs and are currently in clinical trials. However, a lack of knowledge of HDAC biology has made it difficult to predict which tumors will respond to these drugs. HDACs are known to participate in gene repression, but recent work indicates that they are also transcriptional coactivators. Our studies on the mechanism of gene repression through HDAC inhibitors will provide insight into the role of these enzymes as coactivators.
Education: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.