Cloning and characterization of a novel transforming growth factor-beta 1-induced TIAF1 protein that inhibits tumor necrosis factor cytotoxicity

To determine how TGF-beta 1 protects L929 fibroblasts against TNF-alpha cyt otoxicity, we report the isolation and characterization of a novel cDNA enc oding a 12-kDa TGF-beta 1-induced antiapoptotic factor, designated TIAF1. G FP-tagged TIAF1 protein is present mostly in perinuclear and nuclear locati ons. TIAF1 inhibits the cytotoxic effects of TNF-alpha and overexpressed TN F receptor adaptors TRADD, FADD, and RIP. L929 stable transfectants express ing TIAF1 do not have significant changes in the expression of TNF receptor s and effector or regulatory proteins in apoptosis, which may account for t he acquired TNF resistance in these cells. Notably, these cells have a sign ificantly suppressed I kappa B-alpha protein expression, and I kappa B-alph a degradation is blocked when exposing these cells to TNF-alpha. Similarly, stimulation of untransfected L929 cells with TGF-beta 1 results in suppres sion of I kappa B-alpha expression and retarded I kappa B-alpha degradation in response to TNF-alpha. Despite the fact that the mechanism for blocking TNF cytotoxicity is unknown, TIAF1 is apparently involved in TGF-beta 1 in hibition of I kappa B-alpha expression and suppression of TNF-mediated I ka ppa B-alpha degradation. (C) 1998 Academic Press.