title: Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development.
abstract: Signals through the pre-B cell antigen receptor (pre-BCR) and interleukin 7 receptor (IL-7R) coordinate pre-B cell population expansion with subsequent recombination of the locus encoding immunoglobulin kappa-chain (Igk). Although many 'downstream' effectors of each receptor are known, how they integrate to mediate development has remained unclear. Here we report that pre-BCR-mediated activation of the Ras-MEK-Erk signaling pathway silenced transcription of Ccnd3 (encoding cyclin D3) and coordinated exit from the cell cycle with induction of the transcription factor E2A and the initiation of Igk recombination. IL-7R-mediated activation of the transcription factor STAT5 opposed this pathway by promoting Ccnd3 expression and concomitantly inhibiting Igk transcription by binding to the Igk intronic enhancer and preventing E2A recruitment. Our data show how pre-BCR signaling poises pre-B cells to undergo differentiation after escape from IL-7R signaling.
authors.affiliation: Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Malay
authors.initials: M
authors.lastname: Mandal
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Powers
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ochiai
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Kee
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D056743:Cyclin D3; D016213:Cyclins / Q000276:immunology / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D020868:Gene Silencing / Q000276:immunology; D015151:Immunoblotting; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018631:ras Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056743:Cyclin D3; D016213:Cyclins; D048049:Extracellular Signal-Regulated MAP Kinases; D007147:Immunoglobulin Light Chains; D020930:MAP Kinase Kinase Kinases; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D018631:ras Proteins; C534697:Ccnd3 protein, mouse; C075668:Tcf3 protein, mouse