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

Oncogene
B KarakasB H Park

Abstract

Transforming growth factor-beta type 1 (TGF-beta) 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-beta in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-beta is mediated through the proinflammatory cytokine, interleukin-1alpha (IL-1alpha). Using gene expression array analysis, we identified IL-1alpha as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-beta stimulation. Cell proliferation assays verified that recombinant IL-1alpha was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1alpha prevented the growth proliferative effects of TGF-beta. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-beta induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1alpha gene expression. These studies demonstra...Continue Reading

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Citations

Nov 17, 2007·Nature Protocols·Carlo RagoFred Bunz
Dec 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Abde M AbukhdeirBen Ho Park
Nov 13, 2008·Molecular and Cellular Biology·Vladimir L GabaiMichael Y Sherman
Oct 14, 2010·Cellular Signalling·Maozhen TianWilliam P Schiemann
Apr 17, 2015·BMC Medical Genomics·Frederick S VarnChao Cheng
May 15, 2010·Molecular Oncology·Per E Lønning
Jan 23, 2020·PloS One·Michelle A NottScott W Tighe
Jul 14, 2021·Communications Biology·Justin ZonnevilleAndrei V Bakin

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