TIAF1 is a TGF-beta 1-induced factor that protects L929 fibroblasts from TNF-mediated apoptosis. In contrast, overexpressed TIAF1 induces growth inhibition and apoptosis of monocytic U937 and various nonfibroblast cells. TIAF1-mediated apoptosis of U937 cells involves upregulation of p53, p21, and Smad2/4, but downregulation of ERK phosphorylation. To determine whether p53 and TIAF1 functionally interact in regulating cell death, ectopic TIAF1 and p53 were shown to induce apoptosis of U937 cells in both synergistic and antagonistic manners. At optimal levels both TIAF1 and p53 mediated apoptosis cooperatively. Also, both proteins suppressed adherence-independent growth of L929 cells. In contrast, initiation of apoptosis by overexpressed TIAF1 was blocked by low doses of p53, and vice versa. Furthermore, ectopic p53 blocked an ongoing apoptosis in U937 cells stably expressing TIAF1. Yeast two-hybrid analyses failed to demonstrate the binding of p53 with TIAF1, suggesting an unidentified protein that links the p53/TIFA1 interaction. Suppression of TIAF1 expression by siRNA could not inhibit Ser15 phosphorylation in p53 in response to UV and etoposide. However, nuclear translocation of these Ser15-phosphorylated p53 was significantly reduced in TIAF1-silenced cells. Taken together, TIAF1 and p53 functionally interact in regulating apoptosis, and TIAF1 is likely to participate in the nuclear translocation of activated p53.

TGF-beta induces growth suppression and apoptosis of various types of cells, but supports fibroblast growth. We previously isolated TIAF1 (TGF-beta1-induced antiapoptotic factor 1), which protects murine L929 fibroblasts from TNF cytotoxicity. Here, we show that TIAF1 induced growth inhibition and apoptosis of monocytic U937 and other types of cells. In contrast, like TGF-beta1, TIAF1 supported transforming growth of L929 fibroblasts. TIAF1 increased the expression of p53, Cip1/p21, and Smad proteins; suppressed ERK phosphorylation; and altered TGF-beta1-mediated Smad2/3 phosphorylation in U937 cells. Antisense TIAF1 mRNA significantly enhanced the proliferation of mink lung Mv1Lu epithelial cells. Together, these observations indicate that TIAF1 participates in the TGF-beta-mediated growth regulation.