Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells.
Oncogene
; 25(40): 5561-9, 2006 Sep 07.
Article
em En
| MEDLINE
| ID: mdl-16619041
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.
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Base de dados:
MEDLINE
Assunto principal:
Sistemas do Segundo Mensageiro
/
Fator de Crescimento Transformador beta
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Interleucina-1
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Inibidor de Quinase Dependente de Ciclina p21
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article