title: N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.
abstract: Iron is critical for cellular proliferation and its depletion leads to a suppression of both DNA synthesis and global translation. These observations suggest that iron depletion may trigger a cellular "stress response". A canonical response of cells to stress is the formation of stress granules, which are dynamic cytoplasmic aggregates containing stalled pre-initiation complexes that function as mRNA triage centers. By differentially prioritizing mRNA translation, stress granules allow for the continued and selective translation of stress response proteins. Although the multi-subunit eukaryotic initiation factor 3 (eIF3) is required for translation initiation, its largest subunit, eIF3a, may not be essential for this activity. Instead, eIF3a is a vital constituent of stress granules and appears to act, in part, by differentially regulating specific mRNAs during iron depletion. Considering this, we investigated eIF3a's role in modulating iron-regulated genes/proteins that are critically involved in proliferation and metastasis. In this study, eIF3a was down-regulated and recruited into stress granules by iron depletion as well as by the classical stress-inducers, hypoxia and tunicamycin. Iron depletion also increased expression of the metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), and a known downstream repressed target of eIF3a, namely the cyclin-dependent kinase inhibitor, p27(kip1). To determine if eIF3a regulates NDRG1 expression, eIF3a was inducibly over-expressed or ablated. Importantly, eIF3a positively regulated NDRG1 expression and negatively regulated p27(kip1) expression during iron depletion. This activity of eIF3a could be due to its recruitment to stress granules and/or its ability to differentially regulate mRNA translation during cellular stress. Additionally, eIF3a positively regulated proliferation, but negatively regulated cell motility and invasion, which may be due to the eIF3a-dependent changes in expression of NDRG1 and p27(kip1) observed under these conditions.
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia. darius.lane@sydney.edu.au
authors: Darius J R
authors: DJ
authors: Lane
authors: Federica
authors: F
authors: Saletta
authors: Yohan
authors: Y
authors: Suryo Rahmanto
authors: Zaklina
authors: Z
authors: Kovacevic
authors: Des R
authors: DR
authors: Richardson
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D000090463:Iron Deficiencies; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D039621:Eukaryotic Initiation Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D012333:RNA, Messenger; D014415:Tunicamycin; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C436291:CDKN1B protein, human; C105988:EIF3A protein, human