{"id":{"repo_id":"aachen","oai_identifier":"oai:publications.rwth-aachen.de:51420"},"canonical_url":"https://search.dev.ndltd.org/etd/aachen/oai:publications.rwth-aachen.de:51420","repository":{"repo_id":"aachen","name":"RWTH Aachen University","base_url":"https://publications.rwth-aachen.de/oai2d"},"display":{"title":"Molecular analysis of the role of Caspase-8 during liver regeneration and tumorigenesis","abstract":"Binding of the cytokine TNF-alpha to TNF-Receptor 1 mediates pleiotropic effects via two different signaling complexes. Complex-I triggers activation of NF-kappaB and activation of c-Jun N-terminal kinases (JNK) leading to inflammation and/ or cell proliferation, whereas complex-II induces apoptosis through Caspase-8. TNF signaling is crucial for the priming phase of liver regeneration following partial hepatectomy (PH) which directly contributes to gene activation of Cyclin D via NF-kappaB, c-Jun/ AP-1 and E2F1. The aim of the present study was to investigate the consequences of Caspase-8 deletion for TNF signaling during liver regeneration and termination as well as the role of Caspase-8 for initiation and development of hepatocellular carcinoma. Consequently, animals expressing Caspase-8 (f/f) on a regular level or mice deleted (delta) in Caspase-8 were generated to define the role of Caspase-8 during TNF-mediated signaling and subjected to 2/3 PH. Cessation of liver regeneration was observed in the same manner in both genotypes at equal time points clearly indicating that the function of Caspase-8 is dispensable for the process of termination. Surprisingly, animals with deleted Caspase-8 were more prone to TNF-mediated NF-kappaB and c-Jun/ AP-1 activation due to advantageous formation of complex-I subsequently leading to earlier onset of cell cycle progression. For the characterization of Casp8deltahep mice in genetic models of hepatocarcinogenesis, a standardized protocol for the application of magnetic resonance imaging (MRI) on genetically modified mice was established. Using this technique and conventional methods it was demonstrated that concomitant Caspase-8 ablation and c-myc over-expression in murine livers (Casp8deltahepalb-myctg) caused delayed tumor development but accelerated progression of HCC when compared to alb-myctg mice. These findings provide strong evidence for a protective function of Caspase-8 in hepatocellular carcinogenesis. In summary, it was demonstrated that Caspase-8 mediates not only pro-apoptotic, but also non-apoptotic functions as it contributes to the proper assembly of TNF- complex-I formation. Thus, ablation of Caspase-8 results in aberrant complex-I formation and subsequently accelerated NF-kappaB and JNK activation eventually leading to earlier Cyclin D expression and induction of cell cycle activity.","abstract_html":"Binding of the cytokine TNF-alpha to TNF-Receptor 1 mediates pleiotropic effects via two different signaling complexes. Complex-I triggers activation of NF-kappaB and activation of c-Jun N-terminal kinases (JNK) leading to inflammation and/ or cell proliferation, whereas complex-II induces apoptosis through Caspase-8. TNF signaling is crucial for the priming phase of liver regeneration following partial hepatectomy (PH) which directly contributes to gene activation of Cyclin D via NF-kappaB, c-Jun/ AP-1 and E2F1. The aim of the present study was to investigate the consequences of Caspase-8 deletion for TNF signaling during liver regeneration and termination as well as the role of Caspase-8 for initiation and development of hepatocellular carcinoma. Consequently, animals expressing Caspase-8 (f/f) on a regular level or mice deleted (delta) in Caspase-8 were generated to define the role of Caspase-8 during TNF-mediated signaling and subjected to 2/3 PH. Cessation of liver regeneration was observed in the same manner in both genotypes at equal time points clearly indicating that the function of Caspase-8 is dispensable for the process of termination. Surprisingly, animals with deleted Caspase-8 were more prone to TNF-mediated NF-kappaB and c-Jun/ AP-1 activation due to advantageous formation of complex-I subsequently leading to earlier onset of cell cycle progression. For the characterization of Casp8deltahep mice in genetic models of hepatocarcinogenesis, a standardized protocol for the application of magnetic resonance imaging (MRI) on genetically modified mice was established. Using this technique and conventional methods it was demonstrated that concomitant Caspase-8 ablation and c-myc over-expression in murine livers (Casp8deltahepalb-myctg) caused delayed tumor development but accelerated progression of HCC when compared to alb-myctg mice. These findings provide strong evidence for a protective function of Caspase-8 in hepatocellular carcinogenesis. In summary, it was demonstrated that Caspase-8 mediates not only pro-apoptotic, but also non-apoptotic functions as it contributes to the proper assembly of TNF- complex-I formation. Thus, ablation of Caspase-8 results in aberrant complex-I formation and subsequently accelerated NF-kappaB and JNK activation eventually leading to earlier Cyclin D expression and induction of cell cycle activity.","abstract_has_math":false,"creators":["Freimuth, Julia"],"institution":"Publikationsserver der RWTH Aachen University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Liedtke, Christian"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2009,"date_issued":"2009","date_published":"2009","updated_at":"2026-07-30T19:40:33Z","subjects":["info:eu-repo/classification/ddc/610","Apoptosis","Leberresektion","Regeneration","NMR-Tomographie","Medizin","Magnetresonanztomographie","MRT","Hepatozelluläres Karzinom","magnetic resonance imaging","MRI","Hepatocellular carcinoma"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22"],"render_values":[{"text":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22","href":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22","code":true}]}]},"links":{"outbound_url":"https://publications.rwth-aachen.de/record/51420","outbound_label":"Repository record","outbound_source":"dc:identifier"},"source_record":{"url":"https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51420","prefix":"oai_dc"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Liedtke, Christian"]},{"key":"dc:creator","label":"Author","values":["Freimuth, Julia"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:coverage","label":"Dc Coverage","values":["DE"]},{"key":"dc:date","label":"Dc Date","values":["2009"]},{"key":"dc:publisher","label":"Institution","values":["Publikationsserver der RWTH Aachen University"]},{"key":"dc:relation","label":"Dc Relation","values":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-30091"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis","info:eu-repo/semantics/publishedVersion"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["info:eu-repo/classification/ddc/610","Apoptosis","Leberresektion","Regeneration","NMR-Tomographie","Medizin","Magnetresonanztomographie","MRT","Hepatozelluläres Karzinom","magnetic resonance imaging","MRI","Hepatocellular carcinoma"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/record/51420","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Binding of the cytokine TNF-alpha to TNF-Receptor 1 mediates pleiotropic effects via two different signaling complexes. Complex-I triggers activation of NF-kappaB and activation of c-Jun N-terminal kinases (JNK) leading to inflammation and/ or cell proliferation, whereas complex-II induces apoptosis through Caspase-8. TNF signaling is crucial for the priming phase of liver regeneration following partial hepatectomy (PH) which directly contributes to gene activation of Cyclin D via NF-kappaB, c-Jun/ AP-1 and E2F1. The aim of the present study was to investigate the consequences of Caspase-8 deletion for TNF signaling during liver regeneration and termination as well as the role of Caspase-8 for initiation and development of hepatocellular carcinoma. Consequently, animals expressing Caspase-8 (f/f) on a regular level or mice deleted (delta) in Caspase-8 were generated to define the role of Caspase-8 during TNF-mediated signaling and subjected to 2/3 PH. Cessation of liver regeneration was observed in the same manner in both genotypes at equal time points clearly indicating that the function of Caspase-8 is dispensable for the process of termination. Surprisingly, animals with deleted Caspase-8 were more prone to TNF-mediated NF-kappaB and c-Jun/ AP-1 activation due to advantageous formation of complex-I subsequently leading to earlier onset of cell cycle progression. For the characterization of Casp8deltahep mice in genetic models of hepatocarcinogenesis, a standardized protocol for the application of magnetic resonance imaging (MRI) on genetically modified mice was established. Using this technique and conventional methods it was demonstrated that concomitant Caspase-8 ablation and c-myc over-expression in murine livers (Casp8deltahepalb-myctg) caused delayed tumor development but accelerated progression of HCC when compared to alb-myctg mice. These findings provide strong evidence for a protective function of Caspase-8 in hepatocellular carcinogenesis. In summary, it was demonstrated that Caspase-8 mediates not only pro-apoptotic, but also non-apoptotic functions as it contributes to the proper assembly of TNF- complex-I formation. Thus, ablation of Caspase-8 results in aberrant complex-I formation and subsequently accelerated NF-kappaB and JNK activation eventually leading to earlier Cyclin D expression and induction of cell cycle activity."]},{"key":"dc:source","label":"Dc Source","values":["Aachen : Publikationsserver der RWTH Aachen University XIII, 125 Bl. : Ill., graph. Darst. (2009). = Aachen, Techn. Hochsch., Diss., 2009"]},{"key":"dc:title","label":"Title","values":["Molecular analysis of the role of Caspase-8 during liver regeneration and tumorigenesis"]}]}],"canonical_facts":{"dc:contributor":["Liedtke, Christian"],"dc:coverage":["DE"],"dc:creator":["Freimuth, Julia"],"dc:date":["2009"],"dc:description":["Binding of the cytokine TNF-alpha to TNF-Receptor 1 mediates pleiotropic effects via two different signaling complexes. Complex-I triggers activation of NF-kappaB and activation of c-Jun N-terminal kinases (JNK) leading to inflammation and/ or cell proliferation, whereas complex-II induces apoptosis through Caspase-8. TNF signaling is crucial for the priming phase of liver regeneration following partial hepatectomy (PH) which directly contributes to gene activation of Cyclin D via NF-kappaB, c-Jun/ AP-1 and E2F1. The aim of the present study was to investigate the consequences of Caspase-8 deletion for TNF signaling during liver regeneration and termination as well as the role of Caspase-8 for initiation and development of hepatocellular carcinoma. Consequently, animals expressing Caspase-8 (f/f) on a regular level or mice deleted (delta) in Caspase-8 were generated to define the role of Caspase-8 during TNF-mediated signaling and subjected to 2/3 PH. Cessation of liver regeneration was observed in the same manner in both genotypes at equal time points clearly indicating that the function of Caspase-8 is dispensable for the process of termination. Surprisingly, animals with deleted Caspase-8 were more prone to TNF-mediated NF-kappaB and c-Jun/ AP-1 activation due to advantageous formation of complex-I subsequently leading to earlier onset of cell cycle progression. For the characterization of Casp8deltahep mice in genetic models of hepatocarcinogenesis, a standardized protocol for the application of magnetic resonance imaging (MRI) on genetically modified mice was established. Using this technique and conventional methods it was demonstrated that concomitant Caspase-8 ablation and c-myc over-expression in murine livers (Casp8deltahepalb-myctg) caused delayed tumor development but accelerated progression of HCC when compared to alb-myctg mice. These findings provide strong evidence for a protective function of Caspase-8 in hepatocellular carcinogenesis. In summary, it was demonstrated that Caspase-8 mediates not only pro-apoptotic, but also non-apoptotic functions as it contributes to the proper assembly of TNF- complex-I formation. Thus, ablation of Caspase-8 results in aberrant complex-I formation and subsequently accelerated NF-kappaB and JNK activation eventually leading to earlier Cyclin D expression and induction of cell cycle activity."],"dc:identifier":["https://publications.rwth-aachen.de/record/51420","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22"],"dc:language":["eng"],"dc:publisher":["Publikationsserver der RWTH Aachen University"],"dc:relation":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-30091"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:source":["Aachen : Publikationsserver der RWTH Aachen University XIII, 125 Bl. : Ill., graph. Darst. (2009). = Aachen, Techn. 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