title: The eIF4G homolog DAP5/p97 supports the translation of select mRNAs during endoplasmic reticulum stress.
abstract: DAP5/p97 is a member of the eIF4G family of translation initiation factors that has been suggested to play an important role in the translation of select messenger RNA molecules. We have shown previously that the caspase-cleaved form of DAP5/p97, termed p86, is required for the induction of the endoplasmic reticulum (ER)-stress-responsive internal ribosome entry site (IRES) of the caspase inhibitor HIAP2. We show here that expression of DAP5/p97 is enhanced during ER stress by selective recruitment of DAP5/p97 mRNA into polysomes via the DAP5/p97 IRES. Importantly, enhanced translation mediated by the DAP5/p97 IRES is dependent on DAP5/p97 itself, thus providing a positive feedback loop. In addition, we show that activation of DAP5/p97 and HIAP2 IRES during ER stress requires DAP5/p97. Significantly, the induction of DAP5/p97 during ER stress is caspase-independent, whereas the induction of HIAP2 requires proteolytic processing of DAP5/p97. Thus, DAP5/p97 is a translational activator that selectively modulates translation of specific mRNAs during conditions of cellular stress in both a caspase-dependent and caspase-independent manner.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H 8L1 Canada.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lewis
authors.forename: Sonia
authors.initials: S
authors.lastname: Cerquozzi
authors.forename: Tyson E
authors.initials: TE
authors.lastname: Graber
authors.forename: Nicoleta Hosszu
authors.initials: NH
authors.lastname: Ungureanu
authors.forename: Meghan
authors.initials: M
authors.lastname: Andrews
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
mesh_terms: D020121:5' Untranslated Regions / Q000737:chemistry*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D010448:Peptide Initiation Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; D051034:Inhibitor of Apoptosis Proteins; D010448:Peptide Initiation Factors; C104836:eukaryotic translational regulator p97; D020169:Caspases