{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/901"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/901","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"The Role of Foxo Transcription Factors in B Cell Development and Activation","abstract":"A functional immune system depends on a diverse, self tolerant B cell repertoire. Mature B cells distributed throughout secondary lymphoid organs respond to antigenic stimuli by dividing and differentiating into plasma cells and other effector cell types. Signaling from the B cell receptor (BCR) plays a critical role at several points during this developmental process. Cell survival, proliferation, differentiation, death, anergy, and receptor editing may occur in response to BCR stimulation. A variety of factors, including signal strength and duration, cytokine presence, and co-stimulation determine the ultimate B cell fate. In this thesis, the roles Foxo transcription factors play in maintaining B cell homeostasis will be explored. Foxo1, Foxo3, and Foxo4 have both anti-mitogenic and pro-apoptotic properties. The transcription factors are posttranslationally controlled via Akt. When a mature B lymphocyte is stimulated through the BCR, Akt-mediated phosphorylation of Foxos results in their exclusion from the nucleus. In the absence of Foxo nuclear activity, the B cell progresses into the cell cycle. We have discovered a second PI3K-dependent means of control for Foxos, at the level of mRNA expression. Downstream of the BCR, this means of control is unique and functionally relevant. Mature B cells proliferating in response to anti-IgM downregulate Foxo mRNA expression. This is via activation of the PI3K/Btk/BLNK/PLC-gamma2 pathway. Conversely, Foxo mRNA expression is upregulated in immature B cells, both when the tonic/basal signal through the BCR is disrupted and when the BCR is engaged with anti-IgM. Overexpression of Foxo3 mRNA in an immature B cell line promotes anti- IgM induced apoptosis. Primary immature B cells from Foxo3-/- mice have decreased apoptotic response to BCR crosslinking. Thus, at the immature stage of development our work has revealed a potential role for Foxo3 in promoting clonal deletion. Foxo3-/- mice also have reduced frequencies of pre-B and mature recirculating B cells in the blood and bone marrow. The mice demonstrate increased basal levels of IgG2a, IgG3, and IgA. Thus, Foxo3 deficiency affects numerous aspects of B cell development.","abstract_html":"A functional immune system depends on a diverse, self tolerant B cell repertoire. Mature B cells distributed throughout secondary lymphoid organs respond to antigenic stimuli by dividing and differentiating into plasma cells and other effector cell types. Signaling from the B cell receptor (BCR) plays a critical role at several points during this developmental process. Cell survival, proliferation, differentiation, death, anergy, and receptor editing may occur in response to BCR stimulation. A variety of factors, including signal strength and duration, cytokine presence, and co-stimulation determine the ultimate B cell fate. In this thesis, the roles Foxo transcription factors play in maintaining B cell homeostasis will be explored. Foxo1, Foxo3, and Foxo4 have both anti-mitogenic and pro-apoptotic properties. The transcription factors are posttranslationally controlled via Akt. When a mature B lymphocyte is stimulated through the BCR, Akt-mediated phosphorylation of Foxos results in their exclusion from the nucleus. In the absence of Foxo nuclear activity, the B cell progresses into the cell cycle. We have discovered a second PI3K-dependent means of control for Foxos, at the level of mRNA expression. Downstream of the BCR, this means of control is unique and functionally relevant. Mature B cells proliferating in response to anti-IgM downregulate Foxo mRNA expression. This is via activation of the PI3K/Btk/BLNK/PLC-gamma2 pathway. Conversely, Foxo mRNA expression is upregulated in immature B cells, both when the tonic/basal signal through the BCR is disrupted and when the BCR is engaged with anti-IgM. Overexpression of Foxo3 mRNA in an immature B cell line promotes anti- IgM induced apoptosis. Primary immature B cells from Foxo3-/- mice have decreased apoptotic response to BCR crosslinking. Thus, at the immature stage of development our work has revealed a potential role for Foxo3 in promoting clonal deletion. Foxo3-/- mice also have reduced frequencies of pre-B and mature recirculating B cells in the blood and bone marrow. The mice demonstrate increased basal levels of IgG2a, IgG3, and IgA. Thus, Foxo3 deficiency affects numerous aspects of B cell development.","abstract_has_math":false,"creators":["Hinman, Rochelle Marie"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Satterthwaite, Anne B."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-09-30T18:52:39Z","date_published":"2011-09-30T18:52:39Z","updated_at":"2026-07-24T05:52:17Z","subjects":["B-Lymphocyte Subsets","Forkhead Transcription Factors","Homeostasis"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["761079609"],"render_values":[{"text":"761079609","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/901","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Satterthwaite, Anne B."]},{"key":"dc:creator","label":"Author","values":["Hinman, Rochelle Marie"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-09-30T18:52:39Z","2012-12-01T18:52:39Z","2010-01-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["B-Lymphocyte Subsets","Forkhead Transcription Factors","Homeostasis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/901","761079609"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["A functional immune system depends on a diverse, self tolerant B cell repertoire. Mature B cells distributed throughout secondary lymphoid organs respond to antigenic stimuli by dividing and differentiating into plasma cells and other effector cell types. Signaling from the B cell receptor (BCR) plays a critical role at several points during this developmental process. Cell survival, proliferation, differentiation, death, anergy, and receptor editing may occur in response to BCR stimulation. A variety of factors, including signal strength and duration, cytokine presence, and co-stimulation determine the ultimate B cell fate. In this thesis, the roles Foxo transcription factors play in maintaining B cell homeostasis will be explored. Foxo1, Foxo3, and Foxo4 have both anti-mitogenic and pro-apoptotic properties. The transcription factors are posttranslationally controlled via Akt. When a mature B lymphocyte is stimulated through the BCR, Akt-mediated phosphorylation of Foxos results in their exclusion from the nucleus. In the absence of Foxo nuclear activity, the B cell progresses into the cell cycle. We have discovered a second PI3K-dependent means of control for Foxos, at the level of mRNA expression. Downstream of the BCR, this means of control is unique and functionally relevant. Mature B cells proliferating in response to anti-IgM downregulate Foxo mRNA expression. This is via activation of the PI3K/Btk/BLNK/PLC-gamma2 pathway. Conversely, Foxo mRNA expression is upregulated in immature B cells, both when the tonic/basal signal through the BCR is disrupted and when the BCR is engaged with anti-IgM. Overexpression of Foxo3 mRNA in an immature B cell line promotes anti- IgM induced apoptosis. Primary immature B cells from Foxo3-/- mice have decreased apoptotic response to BCR crosslinking. Thus, at the immature stage of development our work has revealed a potential role for Foxo3 in promoting clonal deletion. Foxo3-/- mice also have reduced frequencies of pre-B and mature recirculating B cells in the blood and bone marrow. The mice demonstrate increased basal levels of IgG2a, IgG3, and IgA. Thus, Foxo3 deficiency affects numerous aspects of B cell development."]},{"key":"dc:format","label":"Dc Format","values":["application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/pdf"]},{"key":"dc:title","label":"Title","values":["The Role of Foxo Transcription Factors in B Cell Development and Activation"]}]}],"canonical_facts":{"dc:contributor":["Satterthwaite, Anne B."],"dc:creator":["Hinman, Rochelle Marie"],"dc:date":["2011-09-30T18:52:39Z","2012-12-01T18:52:39Z","2010-01-12"],"dc:description":["A functional immune system depends on a diverse, self tolerant B cell repertoire. Mature B cells distributed throughout secondary lymphoid organs respond to antigenic stimuli by dividing and differentiating into plasma cells and other effector cell types. Signaling from the B cell receptor (BCR) plays a critical role at several points during this developmental process. Cell survival, proliferation, differentiation, death, anergy, and receptor editing may occur in response to BCR stimulation. A variety of factors, including signal strength and duration, cytokine presence, and co-stimulation determine the ultimate B cell fate. In this thesis, the roles Foxo transcription factors play in maintaining B cell homeostasis will be explored. Foxo1, Foxo3, and Foxo4 have both anti-mitogenic and pro-apoptotic properties. The transcription factors are posttranslationally controlled via Akt. When a mature B lymphocyte is stimulated through the BCR, Akt-mediated phosphorylation of Foxos results in their exclusion from the nucleus. In the absence of Foxo nuclear activity, the B cell progresses into the cell cycle. We have discovered a second PI3K-dependent means of control for Foxos, at the level of mRNA expression. Downstream of the BCR, this means of control is unique and functionally relevant. Mature B cells proliferating in response to anti-IgM downregulate Foxo mRNA expression. This is via activation of the PI3K/Btk/BLNK/PLC-gamma2 pathway. Conversely, Foxo mRNA expression is upregulated in immature B cells, both when the tonic/basal signal through the BCR is disrupted and when the BCR is engaged with anti-IgM. Overexpression of Foxo3 mRNA in an immature B cell line promotes anti- IgM induced apoptosis. Primary immature B cells from Foxo3-/- mice have decreased apoptotic response to BCR crosslinking. Thus, at the immature stage of development our work has revealed a potential role for Foxo3 in promoting clonal deletion. Foxo3-/- mice also have reduced frequencies of pre-B and mature recirculating B cells in the blood and bone marrow. The mice demonstrate increased basal levels of IgG2a, IgG3, and IgA. Thus, Foxo3 deficiency affects numerous aspects of B cell development."],"dc:format":["application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/901","761079609"],"dc:language":["en"],"dc:subject":["B-Lymphocyte Subsets","Forkhead Transcription Factors","Homeostasis"],"dc:title":["The Role of Foxo Transcription Factors in B Cell Development and Activation"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-24T05:52:17Z"}