Interferon consensus sequence binding protein-induced cell proliferation is mediated by TGF-Β signaling and p38 MAPK activation

Abstract

Interferon consensus sequence binding protein (ICSBP), also known as interferon regulatory factor (IRF)-8, is a member of the interferon (IFN)-γ regulatory transcription factors. Studies have suggested a connection between TGF-Β signaling and IRFs. Thus, we investigated the effect of ICSBP on transforming growth factor (TGF)-Β signaling in HL-60, an acute promyelocytic leukemia cell line. Stable expression of ICSBP in HL-60 cells resulted in strong induction of TGF-Β receptor expression and activation of non-Smad as well as Smad pathways. ICSBP expression also augmented cell growth. ICSBP knockdown with small interfering RNA (siRNA) attenuated cell growth and decreased TGF-Β receptor I (TGF-ΒRI) expression. In addition, reduction of TGF-ΒRI using siRNA or pharmacological inhibitor reduced growth of ICSBP-expressing cells. ICSBP expression also led to increased phosphorylation and activation of Akt and p38 MAPK. However, p38 MAPK, but not PI3K-Akt, inhibition abrogated ICSBP-mediated proliferation. Furthermore, siRNA knockdown of either ICSBP or TGF-ΒRI resulted in decreased p38 activation. Intriguingly, TGF-Β-activated kinase 1 (TAK-1), which phosphorylates p38, was activated in ICSBP-expressing cells and its activity was reduced by TGF-ΒRI inhibition. Finally, siRNA knockdown of ICSBP or TGF-ΒRI reduced TAK-1 phosphorylation. This study identifies a novel role for ICSBP in regulating cell growth via TGF-Β receptor upregulation and subsequent activation of the TGF-Β receptor/TAK-1/p38 pathway. © 2011 USCAP, Inc All rights reserved.