Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells

B. Karakas, A. Weeraratna, A. Abukhdeir, B. G. Blair, H. Konishi, S. Arena, K. Becker, W. Wood, P. Argani, A. M. De Marzo, K. E. Bachman, B. H. Park

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor-β type 1 (TGF-β) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-β in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-β is mediated through the proinflammatory cytokine, interleukin-1α (IL-1α). Using gene expression array analysis, we identified IL-1α as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-β stimulation. Cell proliferation assays verified that recombinant IL-1α was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1α prevented the growth proliferative effects of TGF-β. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-β induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1α gene expression. These studies demonstrate a novel role for IL-1α in mediating a proliferative response to TGF-β signaling, and suggest that therapies directed against IL-1α could abate the growth proliferative effects of TGF-β without compromising its tumor suppressive function.

Original languageEnglish (US)
Pages (from-to)5561-5569
Number of pages9
JournalOncogene
Volume25
Issue number40
DOIs
StatePublished - Sep 7 2006

Keywords

  • Breast cancer
  • IL-1alpha
  • TGF-beta
  • p21

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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