Protein phosphatase 2A (PP2A) is increased in old murine B cells and mediates p38 MAPK/tristetraprolin dephosphorylation and E47 mRNA instability.
The transcription factor E47, which regulates immunoglobulin class switch in murine splenic B cells, is down-regulated in aged B cells due to reduced mRNA stability. Part of the decreased stability of E47 mRNA is mediated by tristetraprolin (TTP), a physiological regulator of mRNA stability. We have previously shown that TTP mRNA and protein expression are higher in old B cells, and the protein is less phosphorylated in old B cells, both of which lead to more binding of TTP to the 3'-UTR of E47 mRNA, thereby decreasing its stability. PP2A is a protein phosphatase that plays an important role in the regulation of a number of major signaling pathways. Herein we show that not only the amount but also the activity of PP2A is increased in old B cells. As a consequence of this higher phosphatase activity in old B cells, p38 MAPK and TTP (either directly or indirectly by PP2A) are less phosphorylated as compared with young B cells. PP2A dephosphorylation of p38 MAPK and/or TTP likely generates more binding of the hypophosphorylated TTP to the E47 mRNA, inducing its degradation. This mechanism may be at least in part responsible for the age-related decrease in class switch.
Frasca
Daniela
D
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, P.O. Box 016960 (R-138), Miami, FL 33101, USA.
Romero
Maria
M
Landin
Ana Marie
AM
Diaz
Alain
A
Riley
Richard L
RL
Blomberg
Bonnie B
BB
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology*; D016922:Cellular Senescence / Q000276:immunology*; D005260:Female; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000096:biosynthesis*; D020871:RNA Stability; D051820:TCF Transcription Factors / Q000235:genetics*; D058125:Transcription Factor 7-Like 1 Protein; D051816:Tristetraprolin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D008070:Lipopolysaccharides; D051820:TCF Transcription Factors; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D051816:Tristetraprolin; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2