Cloning and characterization of a novel transforming growth factor-beta1-induced TIAF1 protein that inhibits tumor necrosis factor cytotoxicity.

To determine how TGF-beta1 protects L929 fibroblasts against TNF-alpha cytotoxicity, we report the isolation and characterization of a novel cDNA encoding a 12-kDa TGF-beta1-induced antiapoptotic factor, designated TIAF1. GFP-tagged TIAF1 protein is present mostly in perinuclear and nuclear locations. TIAF1 inhibits the cytotoxic effects of TNF-alpha and overexpressed TNF receptor adaptors TRADD, FADD, and RIP. L929 stable transfectants expressing TIAF1 do not have significant changes in the expression of TNF receptors and effector or regulatory proteins in apoptosis, which may account for the acquired TNF resistance in these cells. Notably, these cells have a significantly suppressed IkappaB-alpha protein expression, and IkappaB-alpha degradation is blocked when exposing these cells to TNF-alpha. Similarly, stimulation of untransfected L929 cells with TGF-beta1 results in suppression of IkappaB-alpha expression and retarded IkappaB-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-beta1 inhibition of IkappaB-alpha expression and suppression of TNF-mediated IkappaB-alpha degradation.