{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/35752"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/35752","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"DNA Damage-dependent Regulation and Function of akt-1 in Caenorhabditis elegans","abstract":"The roundworm Caenorhabditis elegans possesses a single, conserved phosphatidylinositol 3-kinase (PI3K) signaling pathway that regulates somatic developmental decisions and lifespan through the Insulin-like receptor tyrosine kinase (RTK) DAF-2, the class I PI3K AGE-1 and the 3-phosphoinositide-dependent protein kinase 1 (PDK1) homologue PDK-1. This pathway ultimately controls the action of Akt homologues on the forkhead transcription factor DAF-16. The C. elegans Akt orthologue akt-1 also negatively regulates the DNA damage-dependent apoptosis of worm germ cells by indirectly interfering with activation of the key transcription factor CEP-1, the sole homologue of p53 in the worm. Because upstream regulation by RTK/PI3K signaling is known to couple with downstream Akt kinase activity, I hypothesized that the worm daf-2/age-1/pdk-1 pathway would function upstream of akt-1/Akt in response to DNA damage. Surprisingly, this was not the case: daf-2/InsR and pdk-1/PDK1 do not function upstream of akt-1/Akt and instead promote DNA damage-induced germ cell apoptosis independently of CEP-1/p53 by regulating the B cell lymphoma (Bcl2) homologue CED-9 and the Apoptotic protease-activating factor 1 (Apaf1)-like adapter protein CED-4, respectively. Furthermore, PDK-1/PDK1 promotes germ cell apoptosis by a mechanism that does not include changes in the subcellular localization or absolute levels of CED-4/Apaf1, but does require the presence of CEP-1/p53. Therefore, daf-2/RTK, pdk-1/PDK1, and cep-1/p53 co-operate from independent pathways to drive germ cell death. The separation of worm Akt function from canonical RTK/PI3K regulation is consistent with the ability of AKT-1 to function without major changes in phosphorylation at threonine 350, a site homologous to Thr308 in mammals. Since this modification is an essential step in the activation of Akt proteins by PDK1, it is likely that damage-dependent germline activity of AKT-1 is controlled by a novel mechanism that does not involve phosphorylation by PDK-1 on key regulatory sites. These data argue that C. elegans re-arranges single homologous components of a signalling pathway to respond to different stimuli in vivo. Finally, I present data identifying the C. elegans ataxia and telangectasia and Rad3-related (ATR) kinase homologue ATL-1 as a potential target of AKT-1. Collectively, my work has uncovered a novel DNA damage-dependent pathway that allows AKT-1 to control CEP-1/p53-dependent apoptosis.","abstract_html":"The roundworm Caenorhabditis elegans possesses a single, conserved phosphatidylinositol 3-kinase (PI3K) signaling pathway that regulates somatic developmental decisions and lifespan through the Insulin-like receptor tyrosine kinase (RTK) DAF-2, the class I PI3K AGE-1 and the 3-phosphoinositide-dependent protein kinase 1 (PDK1) homologue PDK-1. This pathway ultimately controls the action of Akt homologues on the forkhead transcription factor DAF-16. The C. elegans Akt orthologue akt-1 also negatively regulates the DNA damage-dependent apoptosis of worm germ cells by indirectly interfering with activation of the key transcription factor CEP-1, the sole homologue of p53 in the worm. Because upstream regulation by RTK/PI3K signaling is known to couple with downstream Akt kinase activity, I hypothesized that the worm daf-2/age-1/pdk-1 pathway would function upstream of akt-1/Akt in response to DNA damage. Surprisingly, this was not the case: daf-2/InsR and pdk-1/PDK1 do not function upstream of akt-1/Akt and instead promote DNA damage-induced germ cell apoptosis independently of CEP-1/p53 by regulating the B cell lymphoma (Bcl2) homologue CED-9 and the Apoptotic protease-activating factor 1 (Apaf1)-like adapter protein CED-4, respectively. Furthermore, PDK-1/PDK1 promotes germ cell apoptosis by a mechanism that does not include changes in the subcellular localization or absolute levels of CED-4/Apaf1, but does require the presence of CEP-1/p53. Therefore, daf-2/RTK, pdk-1/PDK1, and cep-1/p53 co-operate from independent pathways to drive germ cell death. The separation of worm Akt function from canonical RTK/PI3K regulation is consistent with the ability of AKT-1 to function without major changes in phosphorylation at threonine 350, a site homologous to Thr308 in mammals. Since this modification is an essential step in the activation of Akt proteins by PDK1, it is likely that damage-dependent germline activity of AKT-1 is controlled by a novel mechanism that does not involve phosphorylation by PDK-1 on key regulatory sites. These data argue that C. elegans re-arranges single homologous components of a signalling pathway to respond to different stimuli in vivo. Finally, I present data identifying the C. elegans ataxia and telangectasia and Rad3-related (ATR) kinase homologue ATL-1 as a potential target of AKT-1. Collectively, my work has uncovered a novel DNA damage-dependent pathway that allows AKT-1 to control CEP-1/p53-dependent apoptosis.","abstract_has_math":false,"creators":["Perrin, Andrew"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Molecular and Medical Genetics","school":null,"contributors":[],"advisors":["Derry, William Brent"],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-03","date_published":"2012-03","updated_at":"2026-07-27T21:27:52Z","subjects":["Apoptosis","Radiation"],"languages":["en_ca"],"rights":["Attribution-NonCommercial-NoDerivs 3.0 Unported"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/3.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/35752","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Derry, William Brent"]},{"key":"dc:contributor.department","label":"Department","values":["Molecular and Medical Genetics"]},{"key":"dc:creator","label":"Author","values":["Perrin, Andrew"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2012-03"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2013-07-26T16:44:14Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["WITHHELD_ONE_YEAR","2013-07-26T16:44:14Z"]},{"key":"dc:date.issued","label":"Date","values":["2012-03"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Apoptosis","Radiation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivs 3.0 Unported"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/3.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/35752"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The roundworm Caenorhabditis elegans possesses a single, conserved phosphatidylinositol 3-kinase (PI3K) signaling pathway that regulates somatic developmental decisions and lifespan through the Insulin-like receptor tyrosine kinase (RTK) DAF-2, the class I PI3K AGE-1 and the 3-phosphoinositide-dependent protein kinase 1 (PDK1) homologue PDK-1. This pathway ultimately controls the action of Akt homologues on the forkhead transcription factor DAF-16. The C. elegans Akt orthologue akt-1 also negatively regulates the DNA damage-dependent apoptosis of worm germ cells by indirectly interfering with activation of the key transcription factor CEP-1, the sole homologue of p53 in the worm. Because upstream regulation by RTK/PI3K signaling is known to couple with downstream Akt kinase activity, I hypothesized that the worm daf-2/age-1/pdk-1 pathway would function upstream of akt-1/Akt in response to DNA damage. Surprisingly, this was not the case: daf-2/InsR and pdk-1/PDK1 do not function upstream of akt-1/Akt and instead promote DNA damage-induced germ cell apoptosis independently of CEP-1/p53 by regulating the B cell lymphoma (Bcl2) homologue CED-9 and the Apoptotic protease-activating factor 1 (Apaf1)-like adapter protein CED-4, respectively. Furthermore, PDK-1/PDK1 promotes germ cell apoptosis by a mechanism that does not include changes in the subcellular localization or absolute levels of CED-4/Apaf1, but does require the presence of CEP-1/p53. Therefore, daf-2/RTK, pdk-1/PDK1, and cep-1/p53 co-operate from independent pathways to drive germ cell death. The separation of worm Akt function from canonical RTK/PI3K regulation is consistent with the ability of AKT-1 to function without major changes in phosphorylation at threonine 350, a site homologous to Thr308 in mammals. Since this modification is an essential step in the activation of Akt proteins by PDK1, it is likely that damage-dependent germline activity of AKT-1 is controlled by a novel mechanism that does not involve phosphorylation by PDK-1 on key regulatory sites. These data argue that C. elegans re-arranges single homologous components of a signalling pathway to respond to different stimuli in vivo. Finally, I present data identifying the C. elegans ataxia and telangectasia and Rad3-related (ATR) kinase homologue ATL-1 as a potential target of AKT-1. Collectively, my work has uncovered a novel DNA damage-dependent pathway that allows AKT-1 to control CEP-1/p53-dependent apoptosis."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["DNA Damage-dependent Regulation and Function of akt-1 in Caenorhabditis elegans"]}]}],"canonical_facts":{"dc:contributor.advisor":["Derry, William Brent"],"dc:contributor.department":["Molecular and Medical Genetics"],"dc:creator":["Perrin, Andrew"],"dc:date":["2012-03"],"dc:date.accessioned":["2013-07-26T16:44:14Z"],"dc:date.available":["WITHHELD_ONE_YEAR","2013-07-26T16:44:14Z"],"dc:date.issued":["2012-03"],"dc:description.abstract":["The roundworm Caenorhabditis elegans possesses a single, conserved phosphatidylinositol 3-kinase (PI3K) signaling pathway that regulates somatic developmental decisions and lifespan through the Insulin-like receptor tyrosine kinase (RTK) DAF-2, the class I PI3K AGE-1 and the 3-phosphoinositide-dependent protein kinase 1 (PDK1) homologue PDK-1. This pathway ultimately controls the action of Akt homologues on the forkhead transcription factor DAF-16. The C. elegans Akt orthologue akt-1 also negatively regulates the DNA damage-dependent apoptosis of worm germ cells by indirectly interfering with activation of the key transcription factor CEP-1, the sole homologue of p53 in the worm. Because upstream regulation by RTK/PI3K signaling is known to couple with downstream Akt kinase activity, I hypothesized that the worm daf-2/age-1/pdk-1 pathway would function upstream of akt-1/Akt in response to DNA damage. Surprisingly, this was not the case: daf-2/InsR and pdk-1/PDK1 do not function upstream of akt-1/Akt and instead promote DNA damage-induced germ cell apoptosis independently of CEP-1/p53 by regulating the B cell lymphoma (Bcl2) homologue CED-9 and the Apoptotic protease-activating factor 1 (Apaf1)-like adapter protein CED-4, respectively. Furthermore, PDK-1/PDK1 promotes germ cell apoptosis by a mechanism that does not include changes in the subcellular localization or absolute levels of CED-4/Apaf1, but does require the presence of CEP-1/p53. Therefore, daf-2/RTK, pdk-1/PDK1, and cep-1/p53 co-operate from independent pathways to drive germ cell death. The separation of worm Akt function from canonical RTK/PI3K regulation is consistent with the ability of AKT-1 to function without major changes in phosphorylation at threonine 350, a site homologous to Thr308 in mammals. Since this modification is an essential step in the activation of Akt proteins by PDK1, it is likely that damage-dependent germline activity of AKT-1 is controlled by a novel mechanism that does not involve phosphorylation by PDK-1 on key regulatory sites. These data argue that C. elegans re-arranges single homologous components of a signalling pathway to respond to different stimuli in vivo. Finally, I present data identifying the C. elegans ataxia and telangectasia and Rad3-related (ATR) kinase homologue ATL-1 as a potential target of AKT-1. Collectively, my work has uncovered a novel DNA damage-dependent pathway that allows AKT-1 to control CEP-1/p53-dependent apoptosis."],"dc:description.degree":["PhD"],"dc:identifier.uri":["http://hdl.handle.net/1807/35752"],"dc:language.iso":["en_ca"],"dc:rights":["Attribution-NonCommercial-NoDerivs 3.0 Unported"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/3.0/"],"dc:subject":["Apoptosis","Radiation"],"dc:title":["DNA Damage-dependent Regulation and Function of akt-1 in Caenorhabditis elegans"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:27:52Z"}