title: MicroRNA 155 control of p53 activity is context dependent and mediated by Aicda and Socs1.
abstract: In biological processes, the balance between positive and negative inputs is critical for an effective physiological response and to prevent disease. A case in point is the germinal center (GC) reaction, wherein high mutational and proliferation rates are accompanied by an obligatory suppression of the DNA repair machinery. Understandably, when the GC reaction goes awry, loss of immune cells or lymphoid cancer ensues. Here, we detail the functional interactions that make microRNA 155 (miR-155) a key part of this process. Upon antigen exposure, miR-155(-/-) mature B cells displayed significantly higher double-strand DNA break (DSB) accumulation and p53 activation than their miR-155(+/+) counterparts. Using B cell-specific knockdown strategies, we confirmed the role of the miR-155 target Aicda (activation-induced cytidine deaminase) in this process and, in combination with a gain-of-function model, unveiled a previously unappreciated role for Socs1 in directly modulating p53 activity and the DNA damage response in B lymphocytes. Thus, miR-155 controls the outcome of the GC reaction by modulating its initiation (Aicda) and termination (Socs1/p53 response), suggesting a mechanism to explain the quantitative defect in germinal center B cells found in mice lacking or overexpressing this miRNA.
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors: Hakim
authors: H
authors: Bouamar
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors: Daifeng
authors: D
authors: Jiang
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors: Long
authors: L
authors: Wang
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors: An-Ping
authors: AP
authors: Lin
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors: Manoela
authors: M
authors: Ortega
authors: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas, USA aguiarr@uthscsa.edu.
authors: Ricardo C T
authors: RC
authors: Aguiar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D053903:DNA Breaks, Double-Stranded; D005260:Female; D017353:Gene Deletion; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D006657:Histones; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D034741:RNA, Small Interfering; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
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