Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels

Abstract

Tristetraprolin (TTP) is a RNA binding protein that destabilizes mRNA of factors that up-regulate proliferation, invasiveness and inflammation. Here we show that TTP expression is higher in mammary progenitor cells than in other cell populations, and that reducing its levels impairs mammary gland morphogenesis in vivo and mammosphere formation in culture. Knocking down TTP in stem-like HC11 mouse mammary cell line increased inflammatory cytokine mRNAs and signaling cascades involving NF{kappa}B, STAT3 and MAPK p38 activation, which led to apoptosis. Importantly, TNF overexpression and the consequent p38 phosphorylation would be the leading cause of progenitor cell death upon TTP expression restriction. Taken together, our results reveal the relevance of negative posttranscriptional regulation on TNF, exerted by TTP, for the maintenance of the progenitor cell compartment in the mammary gland.