title: IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells.
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.
authors.affiliation: Laboratory of Immunophysiology, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Wen Hong
authors.initials: WH
authors.lastname: Shen
authors.forename: Steve T
authors.initials: ST
authors.lastname: Jackson
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Broussard
authors.forename: Robert H
authors.initials: RH
authors.lastname: McCusker
authors.forename: Klemen
authors.initials: K
authors.lastname: Strle
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Freund
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000096:biosynthesis*; D051357:Cyclin-Dependent Kinase 2; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007399:Interphase; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2