title: 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.
authors.affiliation: Pediatric Oncology Branch, National Cancer Center, Gyeonggi-do, Korea.
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Sung
authors.forename: Heejung
authors.initials: H
authors.lastname: Kim
authors.forename: Yong-Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Na
authors.forename: Byung-Kiu
authors.initials: BK
authors.lastname: Park
mesh_terms: D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D010766:Phosphorylation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
chemical_list: D017931:DNA Primers; D050835:Interferon Regulatory Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099185:Interferon Regulatory Factor-8