Anthrax Lethal Factor Represses Glucocorticoid and Progesterone Receptor Activity
We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2003-05, Vol.100 (10), p.5706-5711 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Webster, Jeanette I. Tonelli, Leonardo H. Moayeri, Mahtab Simons, S. Stoney Leppla, Stephen H. Sternberg, Esther M. |
| description | We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax. |
| doi_str_mv | 10.1073/pnas.1036973100 |
| format | Article |
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Stoney ; Leppla, Stephen H. ; Sternberg, Esther M.</creator><creatorcontrib>Webster, Jeanette I. ; Tonelli, Leonardo H. ; Moayeri, Mahtab ; Simons, S. Stoney ; Leppla, Stephen H. ; Sternberg, Esther M.</creatorcontrib><description>We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1036973100</identifier><identifier>PMID: 12724519</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Anthrax ; Antigens, Bacterial ; Bacillus anthracis ; Bacterial Toxins - pharmacology ; Biological Sciences ; Cell lines ; Cercopithecus aethiops ; COS Cells ; Dexamethasone - pharmacology ; Enzyme Inhibitors - pharmacology ; Female ; Flavonoids - pharmacology ; Gene Expression Regulation - drug effects ; Hormone receptors ; Kinetics ; Male ; Mice ; Mice, Inbred BALB C ; Mifepristone - pharmacology ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Receptors ; Receptors, Glucocorticoid - antagonists & inhibitors ; Receptors, Progesterone - antagonists & inhibitors ; Recombinant Proteins - antagonists & inhibitors ; Repression ; Standard deviation ; Toxicity ; Toxins ; Transactivation ; Transfection</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-05, Vol.100 (10), p.5706-5711</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-c230cf7ec2be97cf714fa825258cb50df7902d261ffd1cbbf5335184bffd8fd83</citedby><cites>FETCH-LOGICAL-c497t-c230cf7ec2be97cf714fa825258cb50df7902d261ffd1cbbf5335184bffd8fd83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/10.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3147481$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3147481$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12724519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Webster, Jeanette I.</creatorcontrib><creatorcontrib>Tonelli, Leonardo H.</creatorcontrib><creatorcontrib>Moayeri, Mahtab</creatorcontrib><creatorcontrib>Simons, S. Stoney</creatorcontrib><creatorcontrib>Leppla, Stephen H.</creatorcontrib><creatorcontrib>Sternberg, Esther M.</creatorcontrib><title>Anthrax Lethal Factor Represses Glucocorticoid and Progesterone Receptor Activity</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax.</description><subject>Animals</subject><subject>Anthrax</subject><subject>Antigens, Bacterial</subject><subject>Bacillus anthracis</subject><subject>Bacterial Toxins - pharmacology</subject><subject>Biological Sciences</subject><subject>Cell lines</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>Dexamethasone - pharmacology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Flavonoids - pharmacology</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Hormone receptors</subject><subject>Kinetics</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mifepristone - pharmacology</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Receptors</subject><subject>Receptors, Glucocorticoid - antagonists & inhibitors</subject><subject>Receptors, Progesterone - antagonists & inhibitors</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Repression</subject><subject>Standard deviation</subject><subject>Toxicity</subject><subject>Toxins</subject><subject>Transactivation</subject><subject>Transfection</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1P3DAQxS3UChbaMxdEc6q4BPwZxwcOK1RopZVKq_ZsOc6YDcrGwXYQ_Pd1tCu2vVSy5LH8e88zfgidEnxJsGRX42BirlilJCMYH6AFwYqUFVf4HVpgTGVZc8qP0HGMjxhjJWp8iI4IlZQLohbox3JI62BeihWktemLW2OTD8VPGAPECLG46yfrrQ-ps75rCzO0xX3wDxATBD9AJi2Ms2RpU_fcpdcP6L0zfYSPu_0E_b798uvma7n6fvftZrkqLVcylZYybJ0ESxtQMleEO1NTQUVtG4FbJxWmLa2Icy2xTeMEY4LUvMnnOi92gq63vuPUbKC1MKRgej2GbmPCq_am0__eDN1aP_hnTURFK5H1n3f64J-mPI_edNFC35sB_BQ1qSVXXM3g1Ra0wccYwL29QbCeU9BzCnqfQlac_93ant99ewY-7YBZubeb_bSQuMrExf8J7aa-T_CSMnq2RR9jzuGNZYRLXhP2B8Jgp-Q</recordid><startdate>20030513</startdate><enddate>20030513</enddate><creator>Webster, Jeanette I.</creator><creator>Tonelli, Leonardo H.</creator><creator>Moayeri, Mahtab</creator><creator>Simons, S. Stoney</creator><creator>Leppla, Stephen H.</creator><creator>Sternberg, Esther M.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</general><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>7QL</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>20030513</creationdate><title>Anthrax Lethal Factor Represses Glucocorticoid and Progesterone Receptor Activity</title><author>Webster, Jeanette I. ; Tonelli, Leonardo H. ; Moayeri, Mahtab ; Simons, S. Stoney ; Leppla, Stephen H. ; Sternberg, Esther M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-c230cf7ec2be97cf714fa825258cb50df7902d261ffd1cbbf5335184bffd8fd83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Anthrax</topic><topic>Antigens, Bacterial</topic><topic>Bacillus anthracis</topic><topic>Bacterial Toxins - pharmacology</topic><topic>Biological Sciences</topic><topic>Cell lines</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>Dexamethasone - pharmacology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Flavonoids - pharmacology</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Hormone receptors</topic><topic>Kinetics</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mifepristone - pharmacology</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Receptors</topic><topic>Receptors, Glucocorticoid - antagonists & inhibitors</topic><topic>Receptors, Progesterone - antagonists & inhibitors</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Repression</topic><topic>Standard deviation</topic><topic>Toxicity</topic><topic>Toxins</topic><topic>Transactivation</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Webster, Jeanette I.</creatorcontrib><creatorcontrib>Tonelli, Leonardo H.</creatorcontrib><creatorcontrib>Moayeri, Mahtab</creatorcontrib><creatorcontrib>Simons, S. Stoney</creatorcontrib><creatorcontrib>Leppla, Stephen H.</creatorcontrib><creatorcontrib>Sternberg, Esther M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Webster, Jeanette I.</au><au>Tonelli, Leonardo H.</au><au>Moayeri, Mahtab</au><au>Simons, S. Stoney</au><au>Leppla, Stephen H.</au><au>Sternberg, Esther M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anthrax Lethal Factor Represses Glucocorticoid and Progesterone Receptor Activity</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2003-05-13</date><risdate>2003</risdate><volume>100</volume><issue>10</issue><spage>5706</spage><epage>5711</epage><pages>5706-5711</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. 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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Anthrax Antigens, Bacterial Bacillus anthracis Bacterial Toxins - pharmacology Biological Sciences Cell lines Cercopithecus aethiops COS Cells Dexamethasone - pharmacology Enzyme Inhibitors - pharmacology Female Flavonoids - pharmacology Gene Expression Regulation - drug effects Hormone receptors Kinetics Male Mice Mice, Inbred BALB C Mifepristone - pharmacology Mitogen-Activated Protein Kinases - antagonists & inhibitors Receptors Receptors, Glucocorticoid - antagonists & inhibitors Receptors, Progesterone - antagonists & inhibitors Recombinant Proteins - antagonists & inhibitors Repression Standard deviation Toxicity Toxins Transactivation Transfection |
| title | Anthrax Lethal Factor Represses Glucocorticoid and Progesterone Receptor Activity |
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