A molecular mechanism for the increased degradation of E47 mRNA in old murine B cells involves TTP (tristetraprolin) (83.5)

Abstract

Abstract We have previously shown that the E2A-encoded transcription factor E47, which regulates class switch recombination (CSR) 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 cytoplasmic proteins increased in aged activated B cells. This is the first study to show that TTP is involved in the degradation of E47 mRNA TTP binds AU-rich elements in the 3′-untranslated region (3′-UTR) of mRNAs leading to their rapid degradation. We show herein that TTP mRNA and protein expression are induced by LPS, anti-CD40 and to a lesser extent by anti-IgM, in B cells from young and old mice. The level of TTP in old B cells is always higher than that in young B cells. We found 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, therefore decreasing mRNA stability in old B cells. These molecular mechanisms for the regulation of E47 in B cells are important for understanding the control of AID, CSR, and somatic hypermutation of Ig, critical for high affinity Ig and optimal response to pathogens.