Abstract
Abstract Interferon consensus sequence binding protein (ICSBP), also known as IRF-8, is a member of the interferon (IFN)- regulatory factors (IRFs) induced by IFN-γ. ICSBP is mostly associated with differentiation of hematopoietic cells and known as a tumor suppressor. ICSBP contains the conserved transactivation domain which is shared by Smad4, suggesting a possible connection of IRF and TGF-β signaling. To test this connection, ICSBP was stably expressed in acute promyelocytic leukemia cell line, HL-60, that expresses little ICSBP. Although TGF-β receptor expression was undetectable in HL-60 cells, the expression of ICSBP in HL-60 (ICSBP-HL-60) resulted in an increased TGF-β receptor expression. Interestingly, even without TGF-β stimulation, both Smad and non-Smad pathways were activated in ICSBP-HL-60 cells compared with Mock-HL-60 cells, indicating ligand-independent activation of TGF-β receptor signaling. In addition, ICSBP expression augmented cell growth and suppression of ICSBP using siRNA specific for ICSBP abolished TGF-β receptor expression and attenuated cell growth. Consistently, reduction of TGF-βRI using siRNA or TGF-β receptor inhibitor, SB431542, also attenuated growth of ICSBP-HL-60 cells compared with Mock cells. Furthermore, MAPK pathways appeared to be involved in ICSBP-mediated cell growth because MAPKs are activated in ICSBP-HL-60 cells and specific inhibitor of this pathway was able to decrease the growth of ICSBP-HL-60 cells more sensitively than Mock-HL-60 cells. Suppression of ICSBP by siRNA effectively inhibited phosphorylation of MAPKs. All these data suggest that ICSBP up-regulates TGF-β receptor, activates ligand-independent TGF-β mediated signaling pathways, such as MAPKs activation, leading to cell proliferation. This study provides a new function of ICSBP in the regulation of cell proliferation Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1236.
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