Author/Editor		Shen, Wen Hong; Jackson, Steve T; Broussard, Suzzane R; McCusker, Robert H; Strle, Klemen; Freund, Gregory G; Johnson, Rodney W; Dantzer, Robert; Kelley, Keith W
Title		IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells
Type		članek
Source		J Immunol
Vol. and No.		Letnik 172, št. 12
Publication year		2004
Volume		str. 7272-81
Language		eng
Abstract		Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.
Descriptors		CELL CYCLE PROTEINS GENE EXPRESSION REGULATION, NEOPLASTIC BREAST NEOPLASMS DNA-BINDING PROTEINS ENZYME ACTIVATION INSULIN-LIKE GROWTH FACTOR I INTERLEUKIN-1 INTERPHASE PHOSPHORYLATION PROTEIN-SERINE-THREONINE KINASES PROTO-ONCOGENE PROTEINS SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS