Death associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffold eukaryotic initiation factors 4GI and II (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. Despite extensive work describing eIF4GI, an understanding of DAP5 activation is yet to be described.
Here I describe our discovery that DAP5:eIF2β binding is regulated by DAP5 phosphorylation and can be stimulated by specific stimuli including protein kinase C PKC-Raf-ERK1/2 signals, mitosis and hypoxia, wherein DAP5:eIF2β binding determines DAP5’s influence on global and template-specific translation. However, DAP5 depletion causes an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. The hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2), and subsequent ubiquitination and degradation. Furthermore, we found that DAP5 regulates HIF-1α abundance and Akt signaling through DAP5:eIF2β-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurs during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response implying that DAP5:eIF2β binding may describe a conserved mechanism for selective stress induced translation.
","abstract_html":"<p>Death associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffold eukaryotic initiation factors 4GI and II (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. Despite extensive work describing eIF4GI, an understanding of DAP5 activation is yet to be described. </p><p> Here I describe our discovery that DAP5:eIF2β binding is regulated by DAP5 phosphorylation and can be stimulated by specific stimuli including protein kinase C PKC-Raf-ERK1/2 signals, mitosis and hypoxia, wherein DAP5:eIF2β binding determines DAP5’s influence on global and template-specific translation. However, DAP5 depletion causes an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. The hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2), and subsequent ubiquitination and degradation. Furthermore, we found that DAP5 regulates HIF-1α abundance and Akt signaling through DAP5:eIF2β-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurs during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response implying that DAP5:eIF2β binding may describe a conserved mechanism for selective stress induced translation.</p>","abstract_has_math":false,"creators":["Bryant, Jeffrey"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Gromeier, Matthias"],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018","date_published":"2018","updated_at":"2026-07-24T02:07:08Z","subjects":["Molecular biology","DAP5","eIF2β","HIF-1α","Hypoxia","PHD2","Translation initiation"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10161/16934","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Gromeier, Matthias"]},{"key":"dc:creator","label":"Author","values":["Bryant, Jeffrey"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2018-05-31T21:15:29Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2018-05-31T21:15:29Z"]},{"key":"dc:date.issued","label":"Date","values":["2018"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Molecular biology","DAP5","eIF2β","HIF-1α","Hypoxia","PHD2","Translation initiation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10161/16934"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Death associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffold eukaryotic initiation factors 4GI and II (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. Despite extensive work describing eIF4GI, an understanding of DAP5 activation is yet to be described.
Here I describe our discovery that DAP5:eIF2β binding is regulated by DAP5 phosphorylation and can be stimulated by specific stimuli including protein kinase C PKC-Raf-ERK1/2 signals, mitosis and hypoxia, wherein DAP5:eIF2β binding determines DAP5’s influence on global and template-specific translation. However, DAP5 depletion causes an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. The hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2), and subsequent ubiquitination and degradation. Furthermore, we found that DAP5 regulates HIF-1α abundance and Akt signaling through DAP5:eIF2β-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurs during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response implying that DAP5:eIF2β binding may describe a conserved mechanism for selective stress induced translation.
"]},{"key":"dc:title","label":"Title","values":["Regulation of HIF-1α during Hypoxia by DAP5-Induced Translation of PHD2"]}]}],"canonical_facts":{"dc:contributor.advisor":["Gromeier, Matthias"],"dc:creator":["Bryant, Jeffrey"],"dc:date.accessioned":["2018-05-31T21:15:29Z"],"dc:date.available":["2018-05-31T21:15:29Z"],"dc:date.issued":["2018"],"dc:description.abstract":["Death associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffold eukaryotic initiation factors 4GI and II (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. Despite extensive work describing eIF4GI, an understanding of DAP5 activation is yet to be described.
Here I describe our discovery that DAP5:eIF2β binding is regulated by DAP5 phosphorylation and can be stimulated by specific stimuli including protein kinase C PKC-Raf-ERK1/2 signals, mitosis and hypoxia, wherein DAP5:eIF2β binding determines DAP5’s influence on global and template-specific translation. However, DAP5 depletion causes an unanticipated surge of hypoxia-inducible factor 1α (HIF-1α), the transcription factor and master switch of the hypoxia response. The hypoxia response is tempered through HIF-1α hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2), and subsequent ubiquitination and degradation. Furthermore, we found that DAP5 regulates HIF-1α abundance and Akt signaling through DAP5:eIF2β-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurs during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF-1α accumulation and curb the hypoxic response implying that DAP5:eIF2β binding may describe a conserved mechanism for selective stress induced translation.
"],"dc:identifier.uri":["https://hdl.handle.net/10161/16934"],"dc:subject":["Molecular biology","DAP5","eIF2β","HIF-1α","Hypoxia","PHD2","Translation initiation"],"dc:title":["Regulation of HIF-1α during Hypoxia by DAP5-Induced Translation of PHD2"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T02:07:08Z"}