title: The small molecule triclabendazole decreases the intracellular level of cyclic AMP and increases resistance to stress in Saccharomyces cerevisiae.
abstract: The Ras-adenylyl cyclase-protein kinase A nutrient-sensing pathway controls metabolism, proliferation and resistance to stress in Saccharomyces cerevisiae. The genetic disruption of this pathway increases resistance to a variety of stresses. We show here that the pharmacological inhibition of this pathway by the drug triclabendazole increases resistance to oxidants, heat stress and extends the chronological life. Evidence is presented that triclabendazole decreases the intracellular level of cyclic AMP by inhibiting adenylyl cyclase and triggers the parallel rapid translocation of the stress-resistance transcription factor Msn2 from the cytosol into the nucleus, as deduced from experiments employing a strain in which MSN2 is replaced with MSN2-GFP (GFP, green fluorescent protein). Msn2 and Msn4 are responsible for activating the transcription of numerous genes that encode proteins that protect cells from stress. The results are consistent with triclabendazole either inhibiting the association of Ras with adenylyl cyclase or directly inhibiting adenylyl cyclase, which in turn triggers Msn2/4 to enter the nucleus and activate stress-responsible element gene expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Runhua
authors.initials: R
authors.lastname: Shi
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Witt
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D001562:Benzimidazoles / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008136:Longevity / Q000187:drug effects* / Q000502:physiology; D008856:Microscopy, Fluorescence; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D000077682:Triclabendazole
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D001562:Benzimidazoles; D004268:DNA-Binding Proteins; C081935:MSN2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D000077682:Triclabendazole; D000242:Cyclic AMP; D011494:Protein Kinases; C410736:Rim15 protein, S cerevisiae; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases