{"id":{"repo_id":"wustl","oai_identifier":"oai:openscholarship.wustl.edu:etd-1886"},"canonical_url":"https://search.dev.ndltd.org/etd/wustl/oai:openscholarship.wustl.edu:etd-1886","repository":{"repo_id":"wustl","name":"Washington University in St. Louis","base_url":"https://openscholarship.wustl.edu/do/oai/"},"display":{"title":"Genetic Analysis of the PI3K/AKT/mTOR Signaling Pathway","abstract":"Cancer is a leading cause of human death, and it is fundamentally attributable to dysfunctional cell signaling. The PI3K/AKT/mTOR pathway is an important pro-growth intracellular signaling cascade that is often inappropriately activated in a wide array of cancers. Efforts to develop anticancer drugs have therefore focused, in part, on identifying PI3K/AKT/mTOR pathway inhibitors. However, patient response to some such inhibitors is mixed, with some patients experiencing a paradoxical activation of the pathway following treatment. It is therefore necessary to better understand the nature of the PI3K/AKT/mTOR pathway and how it varies in different individuals. The work presented here used cell lines from families to measure the activity of three PI3K/AKT/mTOR pathway members: AKT1, p70S6K and 4E-BP1) in a variety of contexts, including under baseline cell growth conditions and in response to treatment with different PI3K/AKT/mTOR pathway inhibitors. Traditional genetic analyses were used to identify pathway activation phenotypes that were influenced by genetic variation, and genomic regions harboring variation were identified. A new tool for ranking candidate genes was developed and used to select promising genes within these regions for follow-up. Genotyping and association tests of SNPs in these genes identified four variants that were associated with two baseline PI3K/AKT/mTOR pathway activation phenotypes. These represent the first studies to find genetic variants that influence post-translational protein modifications. In addition, the identified SNPs may shed light on normal pathway function as well as new mechanisms for pathway inhibition.","abstract_html":"Cancer is a leading cause of human death, and it is fundamentally attributable to dysfunctional cell signaling. The PI3K/AKT/mTOR pathway is an important pro-growth intracellular signaling cascade that is often inappropriately activated in a wide array of cancers. Efforts to develop anticancer drugs have therefore focused, in part, on identifying PI3K/AKT/mTOR pathway inhibitors. However, patient response to some such inhibitors is mixed, with some patients experiencing a paradoxical activation of the pathway following treatment. It is therefore necessary to better understand the nature of the PI3K/AKT/mTOR pathway and how it varies in different individuals. The work presented here used cell lines from families to measure the activity of three PI3K/AKT/mTOR pathway members: AKT1, p70S6K and 4E-BP1) in a variety of contexts, including under baseline cell growth conditions and in response to treatment with different PI3K/AKT/mTOR pathway inhibitors. Traditional genetic analyses were used to identify pathway activation phenotypes that were influenced by genetic variation, and genomic regions harboring variation were identified. A new tool for ranking candidate genes was developed and used to select promising genes within these regions for follow-up. Genotyping and association tests of SNPs in these genes identified four variants that were associated with two baseline PI3K/AKT/mTOR pathway activation phenotypes. These represent the first studies to find genetic variants that influence post-translational protein modifications. In addition, the identified SNPs may shed light on normal pathway function as well as new mechanisms for pathway inhibition.","abstract_has_math":false,"creators":["Hutz, Janna"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Biology and Biomedical Sciences: Human and Statistical Genetics","degree_department":null,"school":null,"contributors":["Howard McLeod"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-05-24T07:00:00Z","date_published":"2010-05-24T07:00:00Z","updated_at":"2026-07-24T06:13:40Z","subjects":["Biology","Genetics","Bioinformatics","Molecular","AKT","candidate genes","cell signaling","mTOR","PI3K"],"languages":["English (en)"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K7RN35V1"],"render_values":[{"text":"https://doi.org/10.7936/K7RN35V1","href":"https://doi.org/10.7936/K7RN35V1","code":true}]}]},"links":{"outbound_url":"https://openscholarship.wustl.edu/etd/887","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Howard McLeod"]},{"key":"dc:creator","label":"Author","values":["Hutz, Janna"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2013-05-25T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biology and Biomedical Sciences: Human and Statistical Genetics"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology","Genetics","Bioinformatics","Molecular","AKT","candidate genes","cell signaling","mTOR","PI3K"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English (en)"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://openscholarship.wustl.edu/etd/887"]},{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K7RN35V1"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cancer is a leading cause of human death, and it is fundamentally attributable to dysfunctional cell signaling. The PI3K/AKT/mTOR pathway is an important pro-growth intracellular signaling cascade that is often inappropriately activated in a wide array of cancers. Efforts to develop anticancer drugs have therefore focused, in part, on identifying PI3K/AKT/mTOR pathway inhibitors. However, patient response to some such inhibitors is mixed, with some patients experiencing a paradoxical activation of the pathway following treatment. It is therefore necessary to better understand the nature of the PI3K/AKT/mTOR pathway and how it varies in different individuals. The work presented here used cell lines from families to measure the activity of three PI3K/AKT/mTOR pathway members: AKT1, p70S6K and 4E-BP1) in a variety of contexts, including under baseline cell growth conditions and in response to treatment with different PI3K/AKT/mTOR pathway inhibitors. Traditional genetic analyses were used to identify pathway activation phenotypes that were influenced by genetic variation, and genomic regions harboring variation were identified. A new tool for ranking candidate genes was developed and used to select promising genes within these regions for follow-up. Genotyping and association tests of SNPs in these genes identified four variants that were associated with two baseline PI3K/AKT/mTOR pathway activation phenotypes. These represent the first studies to find genetic variants that influence post-translational protein modifications. In addition, the identified SNPs may shed light on normal pathway function as well as new mechanisms for pathway inhibition."]},{"key":"dc:title","label":"Title","values":["Genetic Analysis of the PI3K/AKT/mTOR Signaling Pathway"]}]}],"canonical_facts":{"dc:contributor":["Howard McLeod"],"dc:creator":["Hutz, Janna"],"dc:date.available":["2013-05-25T07:00:00Z"],"dc:description.abstract":["Cancer is a leading cause of human death, and it is fundamentally attributable to dysfunctional cell signaling. The PI3K/AKT/mTOR pathway is an important pro-growth intracellular signaling cascade that is often inappropriately activated in a wide array of cancers. Efforts to develop anticancer drugs have therefore focused, in part, on identifying PI3K/AKT/mTOR pathway inhibitors. However, patient response to some such inhibitors is mixed, with some patients experiencing a paradoxical activation of the pathway following treatment. It is therefore necessary to better understand the nature of the PI3K/AKT/mTOR pathway and how it varies in different individuals. The work presented here used cell lines from families to measure the activity of three PI3K/AKT/mTOR pathway members: AKT1, p70S6K and 4E-BP1) in a variety of contexts, including under baseline cell growth conditions and in response to treatment with different PI3K/AKT/mTOR pathway inhibitors. Traditional genetic analyses were used to identify pathway activation phenotypes that were influenced by genetic variation, and genomic regions harboring variation were identified. A new tool for ranking candidate genes was developed and used to select promising genes within these regions for follow-up. Genotyping and association tests of SNPs in these genes identified four variants that were associated with two baseline PI3K/AKT/mTOR pathway activation phenotypes. These represent the first studies to find genetic variants that influence post-translational protein modifications. In addition, the identified SNPs may shed light on normal pathway function as well as new mechanisms for pathway inhibition."],"dc:identifier":["https://openscholarship.wustl.edu/etd/887"],"dc:identifier.doi":["https://doi.org/10.7936/K7RN35V1"],"dc:language":["English (en)"],"dc:subject":["Biology","Genetics","Bioinformatics","Molecular","AKT","candidate genes","cell signaling","mTOR","PI3K"],"dc:title":["Genetic Analysis of the PI3K/AKT/mTOR Signaling Pathway"],"thesis:degree_discipline":["Biology and Biomedical Sciences: Human and Statistical Genetics"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T06:13:40Z"}