title: Coordinated Regulation of Cap-Dependent Translation and MicroRNA Function by Convergent Signaling Pathways.
abstract: Cell growth and proliferation require the coordinated activation of many cellular processes, including cap-dependent mRNA translation. MicroRNAs oppose cap-dependent translation and set thresholds for expression of target proteins. Emerging data suggest that microRNA function is enhanced by cellular activation due in part to induction of the RNA-induced silencing complex (RISC) scaffold protein GW182. In the current study, we demonstrate that increased expression of GW182 in activated or transformed immune cells results from effects of phosphoinositol 3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) and Jak-Stat-Pim signaling on the translation of GW182 mRNA. Both signaling pathways enhanced polysome occupancy and eukaryotic initiation factor 4E (eIF4E) binding to the 5' 7mG cap of GW182 mRNA. The effect of Jak-Stat-Pim signaling on polysome occupancy and expression of GW182 protein was greater than that of PI3K-Akt-mTOR signaling, likely resulting from enhanced eIF4A-dependent unwinding of G-quadruplexes in the 5' untranslated region of GW182 mRNA. Consistent with this, GW182 expression and microRNA function were reduced by inhibition of mTOR or Pim kinases, translation initiation complex assembly, or eIF4A function. Taken together, these data provide a mechanistic link between microRNA function and cap-dependent translation that allows activated immune cells to maintain microRNA-mediated repression of targets despite enhanced rates of protein synthesis.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott H
authors.identifier: 0000-0001-6857-5554
authors.initials: SH
authors.lastname: Olejniczak
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Gaspare
authors.initials: G
authors.lastname: La Rocca
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Radler
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Egan
authors.affiliation: RNAi Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: RNAi Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Garippa
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA craig@mskcc.org.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020121:5' Untranslated Regions; D001324:Autoantigens; D035683:MicroRNAs; D012315:RNA Caps; D016601:RNA-Binding Proteins; C465663:TNRC6A protein, human; C571198:trinucleotide repeat containing 6a protein, mouse