Protein phosphatase 2A (PP2A) is involved in the age-related down-regulation of E47 mRNA stability (84.14)

Abstract

Abstract We have previously shown that the transcription factor E47, which regulates activation-induced cytidine deaminase (AID) and Immunoglubulin class switch in splenic B cells, is down-regulated in aged murine B cells due to increased E47 mRNA decay. At least part of the decreased stability of E47 mRNA seen in aged B cells is mediated by tristetraprolin (TTP), a physiological regulator of mRNA stability. We found that TTP mRNA and protein expression are higher in old than in young B cells. Both TTP protein expression and function in B cells are dependent upon p38 MAPK and there is less phospho-p38 in old activated B cells. Also there is less phospho-TTP in old than in young splenic activated B cells which leads to more binding of TTP to the 3'-UTR of E47 mRNA, therefore decreasing its stability. PP2A is a serine/threonine protein phosphatase that plays an important role in the regulation of a number of major signaling pathways. We found that not only the amount but also the activity of PP2A is increased in old B cells. By specific inhibition of PP2A we have shown less phospho-p38 MAPK and phospho-TTP in old B cells. PP2A dephosphorylation of either p38 MAPK and/or TTP may account for more binding of the hypophosphorylated TTP to the 3'-UTR of the E47 mRNA, inducing its degradation. This mechanism may be at least in part responsible for the age-related decrease in antibody class switch. This work is supported by NIH AG-23717 (BBB) and by NIH AI-064591 (RLR).