professor of biology
Ph.D., Tufts University, Sackler School
Fields of Interest
Use of the fission yeast Schizosaccharomyces pombe for chemical genetic study of cyclic nucleotide phosphodiesterases (PDEs) and other cAMP pathway components from mammals and pathogens.
How do eukaryotic cells sense their environment and regulate biological processes in response to environmental signals? To address this question, my lab has studied how glucose triggers repression of transcription of the fbp1 gene in the fission yeast Schizosaccharomyces pombe. Combining classical yeast genetics with molecular biology, we identified a number of genes required for both repression and derepression of fbp1 transcription, including almost all of the genes of the cyclic AMP (cAMP) signaling pathway.
We have made use of an fbp1-ura4 reporter and the mutations in the cAMP signaling pathway to develop strains for high throughput screens (HTSs) to identify compounds that inhibit cyclic nucleotide phosphodiesterases (PDEs). PDEs are important drug targets and the compounds we identify could be useful in the treatment of some types of cancer, as well as a large number of inflammatory and neurological diseases and even HIV infection. We have completed HTSs for PDE4, PDE7, PDE8, and PDE11 inhibitors. The compounds identified in these screens are remarkable with respect to their biological activity in mammalian cell-based assays given that they have not yet been subjected to medicinal chemistry to enhance their physiochemical and pharmacokinetic properties. Our strain collection includes strains that express 15 of the 21 mammalian PDE genes (representing ten of the PDE 11 families), as well as three Trypanosome PDE genes.
We have also developed a PKA-repressed fbp1-GFP reporter that allows us to detect small molecules, cloned genes or mutations that reduce PKA activity. We expressed the canine adenylyl cyclase 5 (AC5- one of 10 mammalian proteins that convert ATP to cAMP) together with the human GNAS1 G alpha that binds to and activates ACs. Using our GFP reporter, we can detect both a basal AC5 activity and a GNAS1-stimulated activity. We have since expressed eight other mammalian ACs and have detected both basal and stimulated activity. This now gives us an ability to expand our HTSs to seek small molecules that inhibit GNAS1 or an expressed AC as well as those that stimulate PDE activity. A 100,000 compound screen for such compounds is currently underway.
The Paparazzi of Pombe
Check out my Photo Album of the First International Fission Yeast Meeting held in Edinburgh in September 1999.
I also have Photo Albums for
the Second International Fission Yeast Meeting held in Kyoto in March 2002,
the First East Coast Regional Fission Yeast Meeting held in Worcester, MA in July 2003,
the Third International Fission Yeast Meeting held in San Diego in August 2004,
the Second East Coast Regional Fission Yeast Meeting held in Miami, FL in November 2005,
and the Fourth International Fission Yeast Meeting held in Copenhagen in June 2007, along with my Facebook groups for the Copenhagen Pombe 2007, the Fifth International Fission Yeast Meeting Tokyo Pombe 2009, the Sixth International Fission Yeast Meeting (Boston USA 2011; this group includes photo albums from all of the previous international meetings), and the Seventh International Fission Yeast Meeting (London 2013).
If you have any pictures that you would like to add to these albums, please email them to me or directly add pictures to the Facebook groups.
For other pombe informaton on the web, the best place to start is Susan Forsburg's Lab Page.
Asada R, Takemata N, Hoffman CS, Ohta K, Hirota K. (2014) Antagonistic controls of chromatin and mRNA start site selection by Tup family corepressors and the CCAAT-binding factor Mol Cell Biol. pii: MCB.00924-14. [Epub ahead of print] PMID:25535331
Mudge D.K., Yang F., Currie B.M., Kim J.M., Yeda K., Bashyakarla V.K., Ivey F.D., and Hoffman C.S. (2014). Sck1 negatively-regulates Gpa2-mediated glucose signaling in Schizosaccharomyces pombe. Eukaryot Cell. 2014 Feb;13(2):202-8. doi: 10.1128/EC.00277-13.
Demirbas, D., Wyman, A.R., Shimizu-Albergine, M., Cakici, O., Beavo, J.A., and Hoffman, C.S. (2013). A Yeast-Based High-Throughput Screen Identifies A Phosphodiesterase Inhibitor That Elevates Steroidogenesis In Mouse Leydig Cells Via PDE8 And PDE4 Inhibition. PLoS One. 2013;8(8):e71279. doi: 10.1371/journal.pone.0071279.
de Medeiros, A.S., Magee, A., Nelson, K., Friedberg, L., Trocka, K., and Hoffman, C.S. (2013). Use of PKA-mediated phenotypes for genetic and small molecule screens in Schizosaccharomyces pombe. Biochem Soc Trans. 2013 Dec 1;41(6):1692-5. doi: 10.1042/BST20130159.
Ceyhan O., Birsoy K., and Hoffman C.S. 2012. Identification of biologically active PDE11-selective inhibitors using a yeast-based high throughput screen, Chemistry & Biology, 19:155-163.
Mudge D.K., Hoffman C.A., Lubinski T.J., and Hoffman C.S. 2012. Use of a ura5+-lys7+ cassette to construct unmarked gene knock-ins in Schizosaccharomyces pombe, Current Genetics, 58: 59-64.
Didem Demirbas, Ozge Ceyhan, Arlene R. Wyman and Charles S. Hoffman 2011. A Fission Yeast-based Platform for Phosphodiesterase Inhibitor HTSs and Analyses of Phosphodiesterase Activity, Handbook of Experimental Pharmacology (Houslay, Francis, and Conti eds.) Phosphodiesterases as Drug Targets 2011 (204): 135-149.
Demirbas, D., Ceyhan, O., Wyman, A.R., Ivey, F.D., Allain, C., Wang, L., Sharuk, M.N., Francis, S.H., and Hoffman, C.S. 2011. Use of a Schizosaccharomyces pombe PKA-repressible reporter to study cGMP-metabolising phosphodiesterases. Cellular Signalling. 23(3):594-601. PubMed
Ivey, F.D., Taglia, F.X., Yang, F., Lander, M.M., Kelly, D.A., and Hoffman, C.S. 2010. Activated alleles of the Schizosaccharomyces pombe gpa2+ Gα gene identify residues involved in GDP-GTP exchange. Eukaryotic Cell 9: 626–633. PubMed
Alaamery, M.A., Wyman, A.R., Ivey, F.D., Allain, C., Demirbas, D., Wang, L., Ceyhan, O., and Hoffman, C.S. 2010. New classes of PDE7 inhibitors identified by a fission yeast-based HTS. Journal of Biomolecular Screening 15:359–367. PubMed
Roux, A.E., Leroux, A., Alaamery, M.A., Hoffman, C.S., Chartrand, P., Ferbeyre, G., and Rokeach, L.A. 2009. Pro-aging effects of glucose signaling through a G protein-coupled glucose receptor in fission yeast. PLoS Genetics 5(3): e1000408. PubMed
Hirota, K., Miyoshi, T., Kugou, K., Hoffman, C.S., Shibata, T., and Ohta, K. 2008. Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs. Nature 456: 130–134. PubMed
Leem, Y.-E., Ripmaster, T., Kelly, F., Ebina, H., Heincelman, M., Zhang, K., Grewal, S.I.S., Hoffman, C. S., and Levin, H. L. 2008. The pol II promoters of Schizosaccharomyces pombe are targeted by an LTR retrotransposon that is capable of repairing the promoters it disrupts. Molecular Cell 30: 98–107. PubMed
Alaamery, M.A., and Hoffman, C.S. 2008. Schizosaccharomyces pombe Hsp90/Git10 is required for glucose/cAMP signaling. Genetics 178: 1927–36.
Ivey, F.D., Wang, L., Demirbas, D., Allain, C., Hoffman, C.S. 2008. Development of a fission yeast-based high-throughput screen to identify chemical regulators of cAMP phosphodiesterases. Journal of Biomolecular Screening 13: 62–71. PubMed
Hoffman, C.S. 2007. Propping up our knowledge of G protein signaling pathways: diverse functions of putative noncanonical Gbeta subunits in fungi. Science's STKE 370: 3. PubMed
Kao, R.S., Morreale, E., Wang, L., Ivey, F.D., Hoffman, C.S. 2006. Schizosaccharomyces pombe Git1 is a C2-domain protein required for glucose activation of adenylate cyclase. Genetics 173: 49–61. PubMed
Hoffman, R.L., and Hoffman, C.S. 2006. Cloning the Schizosaccharomyces pombe lys2+ gene and construction of new molecular genetic tools. Current Genetics 49: 414–420.
PubMedWang, L., Griffiths, K., Zhang, Y.H., Ivey, F.D., Hoffman, C.S. 2005. Schizosaccharomyces pombe adenylate cyclase suppressor mutations suggest a role for cAMP phosphodiesterase regulation in feedback control of glucose/cAMP signaling. Genetics 171: 1523–1533. PubMed
Ivey, F.D., and Hoffman, C.S. 2005. Direct activation of fission yeast adenylate cyclase by the Gpa2 Galpha of the glucose signaling pathway. Proceedings of the National Academy of Sciences of the USA 102: 6108–6113. PubMed
Hoffman, C.S. 2005. Except in every detail: comparing and contrasting G-protein signaling in Saccharomyces cerevisiae and Schizosaccharomyces pombe. Eukaryotic Cell 4: 495–503.
Hoffman, C.S. 2005. Glucose sensing via the protein kinase A pathway in Schizosaccharomyces pombe. Biochemical Society Transactions 33: 257–60. PubMed
Stiefel, J., Wang L., Kelly, D.A., Janoo, R.T., Seitz, J., Whitehall, S.K., Hoffman, C.S. 2004. Suppressors of an adenylate cyclase deletion in the fission yeast Schizosaccharomyces pombe. Eukaryotic Cell 3: 610–9. PubMed
Wang, L., Kao, R., Ivey, F.D., Hoffman, C.S. 2004. Strategies for gene disruptions and plasmid constructions in fission yeast. Methods 33: 199–205. PubMed
Hirota, K., Hasemi, T., Yamada, T., Mizuno, K.I., Hoffman, C.S., Shibata, T., Ohta, K. 2004. Fission yeast global repressors regulate the specificity of chromatin alteration in response to distinct environmental stresses. Nucleic Acids Research 32: 855–62. PubMed
Hirota, K., Hoffman, C.S., Shibata, T., Ohta, K. 2003. Fission yeast Tup1-like repressors repress chromatin remodeling at the fbp1+ promoter and the ade6-M26 recombination hotspot. Genetics 165: 505–15. PubMed
Yang, P., Du, H., Hoffman, C.S., Marcus, S. 2003. The phospholipase B homolog Plb1 is a mediator of osmotic stress response and of nutrient-dependent repression of sexual differentiation in the fission yeast Schizosaccharomyces pombe. Molecular Genetics and Genomics 269: 116–25. PubMed
Greenall, A., Hadcroft, A.P., Malakasi, P., Jones, N., Morgan, B.A., Hoffman, C.S., Whitehall, S.K. 2002. Role of fission yeast Tup1-like repressors and Prr1 transcription factor in response to salt stress. Molecular Biology of the Cell 13: 2977–89. PubMed
Schadick, K., Fourcade, H.M., Boumenot, P., Seitz, J.J., Morrell, J.L., Chang, L., Gould, K.L., Partridge, J.F., Allshire, R.C., Kitagawa, K., Hieter, P., and Hoffman, C.S. 2002. Schizosaccharomyces pombe Git7p, a member of the Saccharomyces cerevisiae Sgt1p family, is required for glucose and cAMP signaling, cell wall integrity, and septation. Eukaryotic Cell 1: 558–567. PubMed
Ivey, F.D., and Hoffman, C.S. 2002. Preview: Pseudostructural inhibitors of G protein signaling during development. Developmental Cell 3: 154–155. PubMed
Kelly, D.A., and Hoffman, C.S. 2002. Gap repair transformation in fission yeast to exchange plasmid selectable markers. Biotechniques 33: 978–982. PubMed
Takagi, T., Cho, E.-J., Janoo, R.T.K., Polodny, V., Takase, Y., Keogh, M.-C., Woo, S., Fresco-Cohen, L.D., Hoffman, C.S., and Buratowski, S. 2002. Divergent subunit interactions among fungal mRNA 5'-capping machineries. Eukaryotic Cell 1: 448–457. PubMed
Landry, S., and Hoffman, C.S. 2001. The git5 Gb and git11 Gg form an atypical Gbg dimer acting in the fission yeast glucose/cAMP pathway. Genetics 157: 1159–1168.
Janoo, R.T.K., Neely, L.A., Braun, B.R., Whitehall, S.K., and Hoffman, C.S. 2001. Transcriptional regulators of the Schizosaccharomyces pombe fbp1 gene include two redundant Tup1p-like corepressors and the CCAAT binding factor activation complex. Genetics 157: 1205–1215.
Neely, L.A., and Hoffman, C.S. 2000. PKA and MAPK pathways antagonistically regulate fission yeast fbp1 transcription by employing different modes of action at two upstream activation sites. Molecular and Cellular Biology 20: 6426–6434.
Welton, R.M., and Hoffman, C.S. 2000. Glucose monitoring in fission yeast via the gpa2 G alpha , the git5 G beta, and the git3 putative glucose receptor. Genetics 156: 513–521.
Landry, S., Pettit, M.T., Apolinario, E., and Hoffman, C.S. 2000. The fission yeast git5 gene encodes a Gb subunit required for glucose-triggered adenylate cyclase activation. Genetics 154: 1463–1471.
Hoffman, C.S., and Welton, R. 2000. Mutagenesis and gene cloning in Schizosaccharomyces pombe using nonhomologous plasmid integration and rescue. Biotechniques 28: 532–6, 538, 540.
Dal Santo, P., Blanchard, B., and Hoffman, C.S. 1996. The Schizosaccharomyces pombe pyp1 protein tyrosine phosphatase negatively regulates nutrient monitoring pathways. Journal of Cell Science 109: 1919–1925.
Jin, M., Fujita, M., Culley, B.M., Apolinario, E., Yamamoto, M., Maundrell, K., and Hoffman, C.S. 1995. sck1, a high copy number suppressor of defects in the cAMP-dependent protein kinase pathway in fission yeast, encodes a protein homologous to the Saccharomyces cerevisiae SCH9 kinase. Genetics 140: 457–467.
Nocero, M., Isshiki, T., Yamamoto, M., and Hoffman, C.S. 1994. Glucose repression of fbp1 transcription in Schizosaccharomyces pombe is partially regulated by adenylate cyclase activation by a G protein a subunit encoded by gpa2/git8. Genetics 138: 39–45.
Hoffman, C.S., and Winston, F. 1991. Glucose repression of transcription of the Schizosaccharomyces pombe fbp1 gene occurs by a cAMP signaling pathway. Genes and Development 5: 561–571.