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

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 demonstrate a novel role for IL-1alpha in mediating a proliferative response to TGF-beta signaling, and suggest that therapies directed against IL-1alpha could abate the growth proliferative effects of TGF-beta without compromising its tumor suppressive function.

• Authors: B Karakas, A Weeraratna, A Abukhdeir, B G Blair, H Konishi, S Arena, K Becker, W Wood 3rd, P Argani, A M De Marzo, K E Bachman, B H Park
• Journal: Oncogene (Oncogene) Vol. 25 Issue 40 Pg. 5561-9 (Sep 07 2006) ISSN: 0950-9232 [Print] England
• PMID: 16619041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Interleukin-1
• Nucleic Acid Synthesis Inhibitors
• Proliferating Cell Nuclear Antigen
• Transforming Growth Factor beta
• Dactinomycin

Topics

• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Dactinomycin (pharmacology)
• Humans
• Interleukin-1 (genetics, metabolism)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Oligonucleotide Array Sequence Analysis
• Proliferating Cell Nuclear Antigen (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Second Messenger Systems
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Up-Regulation