MicroRNA 155 control of p53 activity is context dependent and mediated by Aicda and Socs1

Mol Cell Biol. 2015 Apr;35(8):1329-40. doi: 10.1128/MCB.01446-14. Epub 2015 Feb 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Cycle Checkpoints
  • Cells, Cultured
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology*
  • DNA Breaks, Double-Stranded
  • Female
  • Gene Deletion
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Histones / immunology
  • Male
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / immunology*
  • Tumor Suppressor Protein p53 / immunology*
  • Up-Regulation

Substances

  • Histones
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • RNA, Small Interfering
  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Tumor Suppressor Protein p53
  • gamma-H2AX protein, mouse
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase