| Identification of Ald6p as the target of a class of small-molecule suppressors of FK506 and their use in network dissection. | |
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MedLine Citation:
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PMID: 15146068 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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FK506 inhibits the Ca2+/calmodulin-dependent protein phosphatase calcineurin, which plays a critical role in yeast subjected to salt stress. A chemical genetic screen for small molecules that suppress growth inhibition by high NaCl plus FK506 identified a structurally related class of suppressors of FK506 (SFKs) named SFKs 2-4. To identify possible protein targets for these small molecules, a genome-wide screen of approximately 4,700 haploid yeast deletion strains was undertaken for strains showing resistance to high NaCl plus FK506. This screen yielded a number of genes not previously implicated in salt stress, including ALD6, which encodes an NADP(+)-dependent aldehyde dehydrogenase, and UTR1, which encodes an NAD+ kinase. Transcriptional profiling of yeast treated with SFK2 indicated that the SFKs target the Ald6p pathway. In addition, screening of the deletion strains for hypersensitivity to SFK2 yielded ZWF1, encoding glucose-6-phosphate dehydrogenase, which has been shown to play an overlapping role with Ald6p in NADPH production. Furthermore, the SFKs inhibited the activity of Ald6p in vitro. Having established that the SFKs target Ald6p, they were used as tools to implicate systematically other gene products in the Ald6p pathway, including Utr1p, which may function by supplying Ald6p with its NADP+ cofactor. Furthermore, growth improvement by the SFKs on high NaCl plus FK506 was shown to require GPD1, which encodes an NADH-dependent glycerol-3-phosphate dehydrogenase that is important for the production of glycerol in response to osmotic stress. |
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Authors:
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Rebecca A Butcher; Stuart L Schreiber |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. Date: 2004-05-14 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 101 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2004 May |
Date Detail:
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Created Date: 2004-05-26 Completed Date: 2004-07-09 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 7868-73 Citation Subset: IM |
Affiliation:
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Department of Chemistry and Chemical Biology and Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Dehydrogenase
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genetics,
metabolism Aldehyde Oxidoreductases / metabolism* Cell Division / drug effects Gene Expression Profiling Genome, Fungal Glucosephosphate Dehydrogenase / metabolism Glycerol / metabolism Haploidy NADP / metabolism Osmotic Pressure Phosphotransferases (Alcohol Group Acceptor) / genetics, metabolism RNA, Fungal / genetics, metabolism Saccharomyces cerevisiae / cytology, drug effects*, enzymology*, genetics Saccharomyces cerevisiae Proteins / genetics, metabolism Sequence Deletion Sodium Chloride / pharmacology Substrate Specificity Tacrolimus / antagonists & inhibitors*, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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GM38627/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RNA, Fungal; 0/Saccharomyces cerevisiae Proteins; 109581-93-3/Tacrolimus; 53-59-8/NADP; 56-81-5/Glycerol; 7647-14-5/Sodium Chloride; EC 1.1.1.49/Glucosephosphate Dehydrogenase; EC 1.2.-/Aldehyde Oxidoreductases; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 1.2.1.5/acetaldehyde dehydrogenase; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.23/NAD kinase; EC 2.7.1.23/UTR1 protein, S cerevisiae |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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