N-myc Downstream Regulated 1 (NDRG1) Is Regulated by Eukaryotic Initiation Factor 3a (eIF3a) during Cellular Stress Caused by Iron Depletion

被引:61
|
作者
Lane, Darius J. R. [1 ]
Saletta, Federica
Rahmanto, Yohan Suryo
Kovacevic, Zaklina
Richardson, Des R.
机构
[1] Univ Sydney, Dept Pathol, Mol Pharmacol & Pathol Program, Sydney, NSW 2006, Australia
来源
PLOS ONE | 2013年 / 8卷 / 02期
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
PYRIDOXAL ISONICOTINOYL HYDRAZONE; EFFECTIVE ANTIPROLIFERATIVE AGENTS; METASTASIS SUPPRESSOR GENE; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; RIBONUCLEOTIDE REDUCTASE; ENDOTHELIAL-CELLS; MOLECULAR TARGETS; TUMOR-METASTASIS; FACTOR; 1-ALPHA; EXPRESSION;
D O I
10.1371/journal.pone.0057273
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:15
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