IL-1β suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells

Wen Hong Shen, Steve T. Jackson, Suzanne R. Broussard, Robert H. McCusker, Klemen Strle, Gregory G. Freund, Rodney W. Johnson, Robert Dantzer, Keith W. Kelley

Research output: Contribution to journalArticlepeer-review


Cell cycle aberrations occurring at the G1/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1β inhibits insulin-like growth factor (IGF) -I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G0/G1 arrest. Notably, IL-1β 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-1β 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-1β has no effect. IL-1β induces p21Cip1/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-1β; stimulation by growth factors such as IGF-I promotes G1-S phase progression, whereas IL-1β antagonizes IGF-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.

Original languageEnglish (US)
Pages (from-to)7272-7281
Number of pages10
JournalJournal of Immunology
Issue number12
StatePublished - Jun 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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