IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells. Academic Article uri icon

Overview

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

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

publication date

  • June 15, 2004

Research

keywords

  • Breast Neoplasms
  • Cell Cycle Proteins
  • Cyclin A
  • DNA-Binding Proteins
  • Gene Expression Regulation, Neoplastic
  • Interleukin-1
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Transcription Factors

Identity

Scopus Document Identifier

  • 2942556904

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.172.12.7272

PubMed ID

  • 15187102

Additional Document Info

volume

  • 172

issue

  • 12