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alliedacademies
Archives of Industrial Biotechnology | Volume 2
May 14-15, 2018 | Montreal, Canada
World Yeast Congress
The fission yeast Schizosaccharomyces pombe cAMP/PKA
pathway is ideal for chemical genetics as it is not essential,
thus allowing one to replace either the S. pombe adenylyl
cyclase (AC) that produces cAMP or the phosphodiesterase
(PDE) that hydrolyzes cAMP with genes encoding related
proteins from other organisms. Our strain collection includes
strains expressing 15 of the 21 mammalian PDE genes, all
10 of the mammalian AC genes, and both wild type and
mutationally-activated forms of the human GNAS Gα that
stimulates the activity of the mammalian transmembrane
ACs. In addition, the S. pombe fbp1 gene is transcriptionally-
repressed by PKA such that an fbp1-ura4 reporter can
be used to detect PDE inhibitors by their ability to confer
5FOA-resistant growth, while fbp1 -GFP and fbp1 -luciferase
reporters can be used to detect AC and/or GNAS inhibitors
that confer increased reporter expression. One advantage of
this screening platform is that compounds identified in these
screens are cell permeable. In the case of the PDE inhibitors,
hit compounds must be highly selective for binding as a
promiscuously-binding compound would likely inhibit cell
growth. Prior screens for PDE inhibitors have identified PDE4
and PDE7 inhibitors that display anti-inflammatory activity
in mammalian cell culture, a PDE4/7 inhibitor that induces
apoptosis in CLL cells, a PDE4/8 inhibitor that elevates
testosterone production by Leydig cells, and a PDE11
inhibitor that elevates cortisol production by adrenocortical
cells. Our most recent HTS has been for inhibitors of GNAS
or AC9, as the mutationally-activated is found in McCune-
Albright patients, as well as in many patients with pancreatic
intraductal papillary mucinous neoplasms and associated
adenocarcinomas. Current efforts are underway to profile
the activity of these putative AC and GNAS inhibitors.
Speaker Biography
Charles S Hoffman received an SB in Life Sciences from MIT and completed his PhD
in Molecular Biology and Microbiology from the Tufts University Sackler School
of Graduate Biomedical Sciences. He has conducted his Post-doctoral studies at
the Harvard Medical School, Department of Genetics, where he began his studies
of glucose/cAMP signaling and transcriptional regulation of the fbp1 gene in
Schizosaccharomyces pombe. He has been a faculty member of the Boston College,
Biology Department since 1990, and has published more than 60 papers and book
chapters. He is an Associate Editor for Current Genetics and G3 Genes, Genomes,
Genetics, and is a Member of the Luxuriant Flowing Hair Club for Scientists and the
Scotch Malt Whisky Society of America.
e:
Heterologous expression of cyclic nucleotide-metabolizing enzymes for drug discovery using
Schizosaccharomyces pombe and PKA-repressed reporters
Charles S Hoffman
Boston College, USA