-
Notifications
You must be signed in to change notification settings - Fork 0
UseCase10 TCDD
Example of nuclear receptor mediated toxicity
2,3,7,8-Tetrachloro-p-dibenzodioxin (TCDD) is a member of the chemical dioxin family and classified as group 1 human carcinogen by IARC. TCDD is a non-genotoxic carcinogen whose primary mechanism involves acting through binding to the Aryl Hydrocarbon receptor(AhR) -{Boverhof 2005}-. Binding of the AhR receptor results in altered gene expression.
The ligand free Aryl hydrocarbon Receptor (AhR) is located in the cytosol as part of the Aryl hydrocarbon Receptor complex. This complex is composed to two Hsp90 chaperones bound to AhR PAS domains, one prostaglandin E synthase 3 protein, one immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2) bound to AhR nuclear localization sequence, and one AhR-activated 9 (ARA9) -{Carver 1997 Petrulis 2002 Pandini 2009}-. TCDD binding to the AhR ligand binding domain causes XAP2 to dissociate exposing the nuclear localization sequence located in the bHLH region -{Ikuta 1998}-. The TCDD-ArH complex is then localized to the nucleus where the two Hsp90 proteins dissociate from the PAS domains allowing binding of ArNT -{Probst 1993 Carver 1997 Pandini 2009}-. The TCDD-AhR-AnRT complex binds to dioxin-responsive-elements (AhR responsive elements) containing the core 5’-GCGTG-3’ and consensus sequence 5’-T/GNGCGTGA/CG/CA-3’ -{Probst 1993}-.
Representational
Biochemical Protein binding Protein complex parts Molecular complex formation Molecular complex dissociation Cellular localization DNA binding motif and consensus sequences Process rate Expression(language requirements) Symmetry in relationships(binds or is bound by are equivalent) Parthood and modality Functional (Question and Answers) Q. “What complexes involve the aryl hydrocarbon receptor?” A.Ahr-Hsp90-Hsp90-ps23-ara9 complex, TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex, TCDD-AhR-ps23-ara9 complex, TCDD-AhR-ps23-ara9-ARnt complex Query:‘molecular complex’ that ‘has component part’ some ‘aryl hydrocarbon receptor’ Q. “Which mechanism involves the Aryl Hydrocarbon Receptor?” A. “mechanism of AhR mediated toxicity induced by TCDD (2,3,7,8-tetrachloro-p-dibenzodioxin)” Query:‘mechanistic toxicology process specification’ that ‘has part’ some (process that ‘has input’ some (‘molecular complex’ that ‘has component part’ some ‘aryl hydrocarbon receptor’)) Q. “Which chemical(s) does this mechanism involve?” A. “TCDD” Query: *not tested Q. “Which protein does this chemical interact with in this mechanism?” A. “Aryl hydrocarbon receptor” Query: *not tested Q. “Where on this protein does this chemical bind to?” A. “ArH ligand binding domain” Query: *not tested Q. “What process involves the dissociation of Hsp90 from the Aryl hydrcarbon receptor complex?” A. “” Query: *not tested
1. Ligand binding 2. Dissociation of XAP2 from AhR protein complex 3. Conformation change and exposure of nuclear localization signal 4. Nuclear localization 5. Complex formation with ArNT 6. DNA binding 7. Transcriptional activation 8. Carcinogensis ‘Mechanism of AhR mediated toxicity induced by TCDD (2,3,7,8-Tetrachloro-p-dibenzodioxin)’ equivalentTo mechanistic toxicology process specification and (has part some TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex formation) and (has part some TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex xap2 dissociation) and (has part some nuclear localization of TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex) and (has part some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex Hsp90 dissociation) and (has part some TCDD-ArH-ps23-ara9-ARnT complex formation) and (has part some TCDD-AhR-ps23-ara9-ARnT complex DNA binding to dioxin response elements) and (has part some transactivation of dioxin response element containing gene sequences) and (results in some carcinogenesis)
‘carcinogenesis’ equivalentTo disease process and (is result of some mechanism of DNA adduct formation by Benzopyrene)
‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex xap2 dissociation’ equivalentTo molecular complex dissociation and (has target some (XAP2 and (is part of some TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex))) and (has product some XAP2) and (has product some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex)
‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex Hsp90 dissociation’ equivalentTo molecular complex dissociation and (has product some TCDD-AhR-ps23-ara9 complex) and (realizes some (to disassociate and (is disposition of some Hsp90) and (in relation to some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex))) and (has target exactly 2 (Hsp90 and (is component part of some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex)))
‘nuclear localization of TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex’ equivalentTo membrane transport and (has proper part some (process start and (is located in some cytosol) and (has participant some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex) and (precedes some (membrane transport and (is located in some nuclear plasma membrane) and (has agent some nuclear pore) and (precedes some (process end and (is located in some nucleus) and (has participant some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex))) and (has target some TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex)))))
‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex formation’ equivalentTo ‘molecular complex formation’ and (‘is part of’ some ‘Mechanism of AhR mediated toxicity induced by TCDD (2,3,7,8-Tetrachloro-p-dibenzodioxin)’) and (‘has target’ some TCDD) and (‘has target’ some (‘AhR ligand binding domain’ and (‘is component part of’ some ‘AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex’))) and (‘has product’ some ‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex’) and (realizes some (‘to be combined’ and (‘is disposition of’ some TCDD) and (‘in relation to’ some ‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex formation’)))
‘TCDD-AhR-ps23-ara9-ARnT complex DNA binding to dioxin response elements’ equivalentTo molecular complex formation and (has target some TCDD-AhR-ps23-ara9-ARnT complex) and (has target some (dioxin response element and (is component part of some gene))) and (has product some TCDD-AhR-ps23-ara9-ARnT complex DNA bound to dioxin response element)
‘TCDD-ArH-ps23-ara9-ARnT complex formation’ equivalentTo molecular complex formation and (has target some ArNT) and (has target some (PAS domain and (is component part of some (aryl hydrocarbon receptor and (is component part of some TCDD-AhR-ps23-ara9 complex))))) and (has product some TCDD-AhR-ps23-ara9-ARnT complex)
‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex’ equivalentTo molecular complex and (has component part some prostaglandin E synthase 3 protein) and (has component part some ARA9 protein) and (has component part some TCDD) and (has component part some (aryl hydrocarbon receptor and (has component part some (AhR ligand binding domain and (is component part of some aryl hydrocarbon receptor) and (is weakly interacting with some TCDD))))) and (has component part some (XAP2 and (has component part some (protein binding domain and (is component part of some XAP2) and (is weakly interacting with some (AhR nuclear localization sequence and (is component part of some aryl hydrocarbon receptor))))))) and (has component part exactly 2 (Hsp90 and (has component part some (protein binding domain and (is component part of some Hsp90) and (is weakly interacting with some (PAS domain and (is component part of some aryl hydrocarbon receptor)))))))
‘TCDD-AhR-Hsp90-Hsp90-ps23-ara9 complex’ equivalentTo molecular complex and (has component part some prostaglandin E synthase 3 protein) and (has component part some ARA9 protein) and (has component part some TCDD) and (has component part some (aryl hydrocarbon receptor and (has component part some (AhR ligand binding domain and (is weakly interacting with some TCDD))) and (has component part exactly 2 (Hsp90 and (has component part some (protein binding domain and (is weakly interacting with exactly 2 (PAS domain and (is component part of some aryl hydrocarbon receptor)))))))))
‘TCDD-AhR-ps23-ara9 complex’ equivalentTo molecular complex and (has component part some prostaglandin E synthase 3 protein) and (has component part some ARA9 protein) and (has component part some TCDD) and (has component part some (aryl hydrocarbon receptor and (has component part some (AhR ligand binding domain and (is component part of some aryl hydrocarbon receptor) and (is weakly interacting with some TCDD))))) and (has component part some (XAP2 and (has component part some (protein binding domain and (is component part of some XAP2) and (is weakly interacting with some (AhR nuclear localization sequence and (is component part of some aryl hydrocarbon receptor)))))))
‘TCDD’ equivalentTo chemical entity and (is part of some TCDD-AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex formation)
‘AhR-Hsp90-Hsp90-ps23-ara9-xap2 complex’ equivalentTo molecular complex and (has component part some aryl hydrocarbon receptor) and (has component part some prostaglandin E synthase 3 protein) and (has component part some ARA9 protein) and (has component part some (XAP2 and (has component part some (protein binding domain and (is component part of some XAP2) and (is weakly interacting with some (AhR nuclear localization sequence and (is part of some aryl hydrocarbon receptor))))))) and (has component part exactly 2 (Hsp90 and (has component part some (protein binding domain and (is connected to some (PAS domain and (is component part of some aryl hydrocarbon receptor))) and (is component part of some Hsp90)))))
‘TCDD-AhR-ps23-ara9-ARnT complex DNA bound to dioxin response element’ equivalentTo molecular complex and (has component part some TCDD-AhR-ps23-ara9-ARnT complex) and (has component part some (dioxin response element and (is component part of some gene)))
‘TCDD-AhR-ps23-ara9-ARnT complex’ equivalentTo molecular complex and (has component part some prostaglandin E synthase 3 protein) and (has component part some ARA9 protein) and (has component part some TCDD) and (has component part some (aryl hydrocarbon receptor and (has component part some (AhR ligand binding domain and (is component part of some aryl hydrocarbon receptor) and (is weakly interacting with some TCDD))))) and (has component part some (ArNT and (has component part some (protein binding domain and (is component part of some ArNT) and (is weakly interacting with some (PAS domain and (is component part of some aryl hydrocarbon receptor)))))))
‘AhR nuclear localization sequence’ equivalentTo nuclear localization sequence and (is component part of some aryl hydrocarbon receptor)
-{bibliography}-