{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gupta M"],"funding":["Breast Cancer Research Foundation","HHS | NIH | National Institute of General Medical Sciences","HHS | NIH | National Cancer Institute","HHS | NIH | National Center for Advancing Translational Sciences (NCATS)","HHS | NIH | National Cancer Institute (NCI)","HHS | NIH | National Center for Advancing Translational Sciences","HHS | NIH | National Institute of General Medical Sciences (NIGMS)"],"pagination":["e2207898120"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10104532"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["120(15)"],"pubmed_abstract":["Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["eIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells."],"pmcid":["PMC10104532"],"funding_grant_id":["R01CA248397","P30CA016087","BCRF-21-146","T32 CA9161-41","UL1TR00038","R01CA178509","GM066704"],"pubmed_authors":["Katsara O","Geter PA","Walters BA","Schneider RJ","Gupta M","Granados Blanco K"],"additional_accession":[]},"is_claimable":false,"name":"eIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells.","description":"Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Apr","modification":"2024-11-15T21:58:39.701Z","creation":"2024-11-15T21:58:39.701Z"},"accession":"S-EPMC10104532","cross_references":{"pubmed":["37014850"],"doi":["10.1073/pnas.2207898120"]}}