Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo
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Bertal H. Aktas1,2,*, Paula Bordelois2,*, Selen Peker1,3, Sophia Merajver4, Jose A. Halperin1,2
1Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA
2Harvard Medical School, Boston, MA, USA
3Ankara University Biotechnology Institute, Ankara, Turkey
4Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
*These authors have contributed equally to this work
Jose A. Halperin, e-mail: Jose_halperin@hms.harvard.edu
Keywords: BRCA1, EPA, Fish Oil, eIF2·GTP·Met-tRNAi, uORF
Received: November 04, 2014 Accepted: January 09, 2015 Published: February 07, 2015
Most sporadic breast and ovarian cancers express low levels of the breast cancer susceptibility gene, BRCA1. The BRCA1 gene produces two transcripts, mRNAa and mRNAb. mRNAb, present in breast cancer but not in normal mammary epithelial cells, contains three upstream open reading frames (uORFs) in its 5’UTR and is translationally repressed. Comparable tandem uORFs are characteristically seen in mRNAs whose translational efficiency paradoxically increases when the overall translation rate is decreased due to phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α). Here we show fish oil derived eicosopanthenoic acid (EPA) that induces eIF2α phosphorylation translationally up-regulates the expression of BRCA1 in human breast cancer cells. We demonstrate further that a diet rich in EPA strongly induces expression of BRCA1 in human breast cancer xenografts.
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