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dc.contributor.authorEverett, Peter
dc.contributor.authorClish, Clary B.
dc.contributor.authorPolymenis, Michael
dc.contributor.authorRen, Jian-Guo
dc.contributor.authorSeth, Pankaj
dc.contributor.authorSukhatme, Vikas Pandurang
dc.date.accessioned2011-11-17T16:23:14Z
dc.date.issued2010
dc.identifier.citationRen, Jian-Guo, Pankaj Seth, Peter Everett, Clary B. Clish, and Vikas P. Sukhatme. 2010. Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS ONE 5(9): e12520.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5347512
dc.description.abstractMalic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and CO2 and uses NAD as a cofactor. Higher expression of this enzyme correlates with the degree of cell de-differentiation. We found that ME2 is expressed in K562 erythroleukemia cells, in which a number of agents have been found to induce differentiation either along the erythroid or the myeloid lineage. We found that knockdown of ME2 led to diminished proliferation of tumor cells and increased apoptosis in vitro. These findings were accompanied by differentiation of K562 cells along the erythroid lineage, as confirmed by staining for glycophorin A and hemoglobin production. ME2 knockdown also totally abolished growth of K562 cells in nude mice. Increased ROS levels, likely reflecting increased mitochondrial production, and a decreased \(NADPH/NADP^+\) ratio were noted but use of a free radical scavenger to decrease inhibition of ROS levels did not reverse the differentiation or apoptotic phenotype, suggesting that ROS production is not causally involved in the resultant phenotype. As might be expected, depletion of ME2 induced an increase in the \(NAD^+/NADH\) ratio and ATP levels fell significantly. Inhibition of the malate-aspartate shuttle was insufficient to induce K562 differentiation. We also examined several intracellular signaling pathways and expression of transcription factors and intermediate filament proteins whose expression is known to be modulated during erythroid differentiation in K562 cells. We found that silencing of ME2 leads to phospho-ERK1/2 inhibition, phospho-AKT activation, increased GATA-1 expression and diminished vimentin expression. Metabolomic analysis, conducted to gain insight into intermediary metabolic pathways that ME2 knockdown might affect, showed that ME2 depletion resulted in high orotate levels, suggesting potential impairment of pyrimidine metabolism. Collectively our data point to ME2 as a potentially novel metabolic target for leukemia therapy.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pone.0012520en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932743/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectdrug discoveryen_US
dc.subjectcell biologyen_US
dc.subjectcell signalingen_US
dc.subjectcellular death and stress responsesen_US
dc.subjectoncologyen_US
dc.subjectmyeloproliferative disorders, including chronic myeloid leukemiaen_US
dc.titleInduction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2en_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorRen, Jian-Guo
dc.date.available2011-11-17T16:23:14Z
dash.affiliation.otherHMS^Medicine- Beth Israel-Deaconessen_US
dc.identifier.doi10.1371/journal.pone.0012520*
dash.authorsorderedfalse
dash.contributor.affiliatedRen, Jian-Guo
dash.contributor.affiliatedSukhatme, Vikas
dash.contributor.affiliatedSeth, Pankaj


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