TY - JOUR
T1 - MicroRNA 155 control of p53 activity is context dependent and mediated by aicda and Socs1
AU - Bouamar, Hakim
AU - Jiang, Daifeng
AU - Wang, Long
AU - Lin, An Ping
AU - Ortega, Manoela
AU - Aguiar, Ricardo C.T.
N1 - Publisher Copyright:
© 2015, American Society for Microbiology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84925426163&partnerID=8YFLogxK
U2 - 10.1128/MCB.01446-14
DO - 10.1128/MCB.01446-14
M3 - Article
C2 - 25645925
AN - SCOPUS:84925426163
SN - 0270-7306
VL - 35
SP - 1329
EP - 1340
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 8
ER -