Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling
► Transcriptional profiling identifies proteins responding to staurosporine treatment. ► The Neurospora ABC3 protein is a staurosporine transporter. ► Drug combinations lead to synergistic activity against Neurospora crassa and pathogenic fungi. An analysis of the time-dependent genetic response to...
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| Veröffentlicht in: | Fungal genetics and biology 2011-12, Vol.48 (12), p.1130-1138 |
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| creator | Fernandes, Andreia S. Pedro Gonçalves, A. Castro, Ana Lopes, Telma A. Gardner, Rui Louise Glass, N. Videira, Arnaldo |
| description | ► Transcriptional profiling identifies proteins responding to staurosporine treatment. ► The Neurospora ABC3 protein is a staurosporine transporter. ► Drug combinations lead to synergistic activity against
Neurospora crassa and pathogenic fungi.
An analysis of the time-dependent genetic response to the death-inducer staurosporine was performed in
Neurospora crassa by transcriptional profiling. Staurosporine induced two major genes encoding an ABC transporter and a protein with similarity to regulatory subunits of potassium channels. The transcriptional response is dependent on the activity of a novel transcription factor. Deletion mutants in differentially expressed genes displayed altered sensitivity to staurosporine, underscoring significant proteins involved in the response to the drug. A null-mutant of the ABC transporter (abc3) is extremely sensitive to staurosporine, accumulates more staurosporine than the wild type strain and is defective in energy-dependent export of the drug, indicating that the ABC3 protein is the first described staurosporine transporter. It was located in the plasma membrane by immunofluorescence microscopy. The combination of inhibitors of ABC transporters or of potassium channels with staurosporine leads to an enhanced activity against
N. crassa and pathogenic fungi paving the way to the development of more potent and specific antifungals. Our results highlight the general use of transcriptional profiling for the identification of novel proteins involved in cell death and their potential use as drug targets. |
| doi_str_mv | 10.1016/j.fgb.2011.09.004 |
| format | Article |
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Neurospora crassa and pathogenic fungi.
An analysis of the time-dependent genetic response to the death-inducer staurosporine was performed in
Neurospora crassa by transcriptional profiling. Staurosporine induced two major genes encoding an ABC transporter and a protein with similarity to regulatory subunits of potassium channels. The transcriptional response is dependent on the activity of a novel transcription factor. Deletion mutants in differentially expressed genes displayed altered sensitivity to staurosporine, underscoring significant proteins involved in the response to the drug. A null-mutant of the ABC transporter (abc3) is extremely sensitive to staurosporine, accumulates more staurosporine than the wild type strain and is defective in energy-dependent export of the drug, indicating that the ABC3 protein is the first described staurosporine transporter. It was located in the plasma membrane by immunofluorescence microscopy. The combination of inhibitors of ABC transporters or of potassium channels with staurosporine leads to an enhanced activity against
N. crassa and pathogenic fungi paving the way to the development of more potent and specific antifungals. Our results highlight the general use of transcriptional profiling for the identification of novel proteins involved in cell death and their potential use as drug targets.</description><identifier>ISSN: 1087-1845</identifier><identifier>EISSN: 1096-0937</identifier><identifier>DOI: 10.1016/j.fgb.2011.09.004</identifier><identifier>PMID: 22001288</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>4-Aminopyridine ; 4-Aminopyridine - pharmacology ; ABC transporter ; ABC transporters ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; ATP-Binding Cassette Transporters ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Cell death ; Deletion mutant ; drug effects ; Drugs ; fluorescence microscopy ; Fungal Proteins ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Fungi ; Gene Expression ; Gene Expression - drug effects ; Gene Expression Profiling ; gene expression regulation ; Gene Expression Regulation, Fungal ; Gene Expression Regulation, Fungal - drug effects ; Genes, Fungal ; Genes, Fungal - drug effects ; genetics ; Immunofluorescence ; Immunohistochemistry ; In Situ Nick-End Labeling ; major genes ; metabolism ; Microarray Analysis ; Microscopy ; Neurospora crassa ; Neurospora crassa - drug effects ; Neurospora crassa - genetics ; Neurospora crassa - metabolism ; pharmacology ; plasma membrane ; Plasma membranes ; Potassium channels ; Regulatory subunits ; Staurosporine ; Staurosporine - metabolism ; Staurosporine - pharmacology ; transcription (genetics) ; Transcription factors ; Transcription Factors - metabolism ; Transcriptional profiling</subject><ispartof>Fungal genetics and biology, 2011-12, Vol.48 (12), p.1130-1138</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><rights>2011 Elsevier Inc. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-d57ae8b7347c4e2c65f5ebf6387138b7664f29bcb8a971cef3a16068774c8c523</citedby><cites>FETCH-LOGICAL-c539t-d57ae8b7347c4e2c65f5ebf6387138b7664f29bcb8a971cef3a16068774c8c523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.fgb.2011.09.004$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22001288$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fernandes, Andreia S.</creatorcontrib><creatorcontrib>Pedro Gonçalves, A.</creatorcontrib><creatorcontrib>Castro, Ana</creatorcontrib><creatorcontrib>Lopes, Telma A.</creatorcontrib><creatorcontrib>Gardner, Rui</creatorcontrib><creatorcontrib>Louise Glass, N.</creatorcontrib><creatorcontrib>Videira, Arnaldo</creatorcontrib><title>Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling</title><title>Fungal genetics and biology</title><addtitle>Fungal Genet Biol</addtitle><description>► Transcriptional profiling identifies proteins responding to staurosporine treatment. ► The Neurospora ABC3 protein is a staurosporine transporter. ► Drug combinations lead to synergistic activity against
Neurospora crassa and pathogenic fungi.
An analysis of the time-dependent genetic response to the death-inducer staurosporine was performed in
Neurospora crassa by transcriptional profiling. Staurosporine induced two major genes encoding an ABC transporter and a protein with similarity to regulatory subunits of potassium channels. The transcriptional response is dependent on the activity of a novel transcription factor. Deletion mutants in differentially expressed genes displayed altered sensitivity to staurosporine, underscoring significant proteins involved in the response to the drug. A null-mutant of the ABC transporter (abc3) is extremely sensitive to staurosporine, accumulates more staurosporine than the wild type strain and is defective in energy-dependent export of the drug, indicating that the ABC3 protein is the first described staurosporine transporter. It was located in the plasma membrane by immunofluorescence microscopy. The combination of inhibitors of ABC transporters or of potassium channels with staurosporine leads to an enhanced activity against
N. crassa and pathogenic fungi paving the way to the development of more potent and specific antifungals. Our results highlight the general use of transcriptional profiling for the identification of novel proteins involved in cell death and their potential use as drug targets.</description><subject>4-Aminopyridine</subject><subject>4-Aminopyridine - pharmacology</subject><subject>ABC transporter</subject><subject>ABC transporters</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>ATP-Binding Cassette Transporters</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Cell death</subject><subject>Deletion mutant</subject><subject>drug effects</subject><subject>Drugs</subject><subject>fluorescence microscopy</subject><subject>Fungal Proteins</subject><subject>Fungal Proteins - genetics</subject><subject>Fungal Proteins - metabolism</subject><subject>Fungi</subject><subject>Gene Expression</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Profiling</subject><subject>gene expression regulation</subject><subject>Gene Expression Regulation, Fungal</subject><subject>Gene Expression Regulation, Fungal - drug effects</subject><subject>Genes, Fungal</subject><subject>Genes, Fungal - drug effects</subject><subject>genetics</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry</subject><subject>In Situ Nick-End Labeling</subject><subject>major genes</subject><subject>metabolism</subject><subject>Microarray Analysis</subject><subject>Microscopy</subject><subject>Neurospora crassa</subject><subject>Neurospora crassa - drug effects</subject><subject>Neurospora crassa - genetics</subject><subject>Neurospora crassa - metabolism</subject><subject>pharmacology</subject><subject>plasma membrane</subject><subject>Plasma membranes</subject><subject>Potassium channels</subject><subject>Regulatory subunits</subject><subject>Staurosporine</subject><subject>Staurosporine - metabolism</subject><subject>Staurosporine - pharmacology</subject><subject>transcription (genetics)</subject><subject>Transcription factors</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional profiling</subject><issn>1087-1845</issn><issn>1096-0937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxSMEoqXwAbhAbnBJsB3HdoSEhCr-SUUcoGfLccZhVll7sZ2V-u1x2FLBpSePxr95ejOvqp5T0lJCxZtd6-axZYTSlgwtIfxBdU7JIBoydPLhVivZUMX7s-pJSjtSwJ7Tx9UZY6VmSp1X4WuY1sVkDL4Ornarn81SJ_AJMx4x39Q51CmbNYZ0CBE91GPpmThDRj_XhxgyoE81TuAzOoTpDxCNTzbiYRMuggVzuJSBp9UjZ5YEz27fi-r644cfl5-bq2-fvly-v2ps3w25mXppQI2y49JyYFb0rofRiU5J2pW-ENyxYbSjMoOkFlxnqCBCScmtsj3rLqp3J93DOu5hssVcNIs-RNybeKODQf3_j8efeg5H3bGOSC6LwKtbgRh-rZCy3mOysCzGQ1iTHsopFevYRr6-l6RlI94zIjZX9ITacs4Uwd0ZokRvkeqdLpHqLVJNBl0iLTMv_t3kbuJvhgV4eQKcCdrMEZO-_l4UOCFElEv1hXh7IqBc_IgQdbII3sKEEWzWU8B7DPwGuX2-dg</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>Fernandes, Andreia S.</creator><creator>Pedro Gonçalves, A.</creator><creator>Castro, Ana</creator><creator>Lopes, Telma A.</creator><creator>Gardner, Rui</creator><creator>Louise Glass, N.</creator><creator>Videira, Arnaldo</creator><general>Elsevier Inc</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7S9</scope><scope>L.6</scope><scope>8FD</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20111201</creationdate><title>Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling</title><author>Fernandes, Andreia S. ; Pedro Gonçalves, A. ; Castro, Ana ; Lopes, Telma A. ; Gardner, Rui ; Louise Glass, N. ; Videira, Arnaldo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-d57ae8b7347c4e2c65f5ebf6387138b7664f29bcb8a971cef3a16068774c8c523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>4-Aminopyridine</topic><topic>4-Aminopyridine - pharmacology</topic><topic>ABC transporter</topic><topic>ABC transporters</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>ATP-Binding Cassette Transporters</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Cell death</topic><topic>Deletion mutant</topic><topic>drug effects</topic><topic>Drugs</topic><topic>fluorescence microscopy</topic><topic>Fungal Proteins</topic><topic>Fungal Proteins - genetics</topic><topic>Fungal Proteins - metabolism</topic><topic>Fungi</topic><topic>Gene Expression</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression Profiling</topic><topic>gene expression regulation</topic><topic>Gene Expression Regulation, Fungal</topic><topic>Gene Expression Regulation, Fungal - drug effects</topic><topic>Genes, Fungal</topic><topic>Genes, Fungal - drug effects</topic><topic>genetics</topic><topic>Immunofluorescence</topic><topic>Immunohistochemistry</topic><topic>In Situ Nick-End Labeling</topic><topic>major genes</topic><topic>metabolism</topic><topic>Microarray Analysis</topic><topic>Microscopy</topic><topic>Neurospora crassa</topic><topic>Neurospora crassa - drug effects</topic><topic>Neurospora crassa - genetics</topic><topic>Neurospora crassa - metabolism</topic><topic>pharmacology</topic><topic>plasma membrane</topic><topic>Plasma membranes</topic><topic>Potassium channels</topic><topic>Regulatory subunits</topic><topic>Staurosporine</topic><topic>Staurosporine - metabolism</topic><topic>Staurosporine - pharmacology</topic><topic>transcription (genetics)</topic><topic>Transcription factors</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional profiling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fernandes, Andreia S.</creatorcontrib><creatorcontrib>Pedro Gonçalves, A.</creatorcontrib><creatorcontrib>Castro, Ana</creatorcontrib><creatorcontrib>Lopes, Telma A.</creatorcontrib><creatorcontrib>Gardner, Rui</creatorcontrib><creatorcontrib>Louise Glass, N.</creatorcontrib><creatorcontrib>Videira, Arnaldo</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Fungal genetics and biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fernandes, Andreia S.</au><au>Pedro Gonçalves, A.</au><au>Castro, Ana</au><au>Lopes, Telma A.</au><au>Gardner, Rui</au><au>Louise Glass, N.</au><au>Videira, Arnaldo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling</atitle><jtitle>Fungal genetics and biology</jtitle><addtitle>Fungal Genet Biol</addtitle><date>2011-12-01</date><risdate>2011</risdate><volume>48</volume><issue>12</issue><spage>1130</spage><epage>1138</epage><pages>1130-1138</pages><issn>1087-1845</issn><eissn>1096-0937</eissn><abstract>► Transcriptional profiling identifies proteins responding to staurosporine treatment. ► The Neurospora ABC3 protein is a staurosporine transporter. ► Drug combinations lead to synergistic activity against
Neurospora crassa and pathogenic fungi.
An analysis of the time-dependent genetic response to the death-inducer staurosporine was performed in
Neurospora crassa by transcriptional profiling. Staurosporine induced two major genes encoding an ABC transporter and a protein with similarity to regulatory subunits of potassium channels. The transcriptional response is dependent on the activity of a novel transcription factor. Deletion mutants in differentially expressed genes displayed altered sensitivity to staurosporine, underscoring significant proteins involved in the response to the drug. A null-mutant of the ABC transporter (abc3) is extremely sensitive to staurosporine, accumulates more staurosporine than the wild type strain and is defective in energy-dependent export of the drug, indicating that the ABC3 protein is the first described staurosporine transporter. It was located in the plasma membrane by immunofluorescence microscopy. The combination of inhibitors of ABC transporters or of potassium channels with staurosporine leads to an enhanced activity against
N. crassa and pathogenic fungi paving the way to the development of more potent and specific antifungals. Our results highlight the general use of transcriptional profiling for the identification of novel proteins involved in cell death and their potential use as drug targets.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22001288</pmid><doi>10.1016/j.fgb.2011.09.004</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Fungal genetics and biology, 2011-12, Vol.48 (12), p.1130-1138 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 4-Aminopyridine 4-Aminopyridine - pharmacology ABC transporter ABC transporters Apoptosis Apoptosis - drug effects Apoptosis - genetics ATP-Binding Cassette Transporters ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism Cell death Deletion mutant drug effects Drugs fluorescence microscopy Fungal Proteins Fungal Proteins - genetics Fungal Proteins - metabolism Fungi Gene Expression Gene Expression - drug effects Gene Expression Profiling gene expression regulation Gene Expression Regulation, Fungal Gene Expression Regulation, Fungal - drug effects Genes, Fungal Genes, Fungal - drug effects genetics Immunofluorescence Immunohistochemistry In Situ Nick-End Labeling major genes metabolism Microarray Analysis Microscopy Neurospora crassa Neurospora crassa - drug effects Neurospora crassa - genetics Neurospora crassa - metabolism pharmacology plasma membrane Plasma membranes Potassium channels Regulatory subunits Staurosporine Staurosporine - metabolism Staurosporine - pharmacology transcription (genetics) Transcription factors Transcription Factors - metabolism Transcriptional profiling |
| title | Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling |
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