tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

The transforming growth factor type β-1 (TGF-β) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IκB kinase α (IKKα) also acts as a tumor suppressor in stratified epithelia, and its express...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-11, Vol.105 (44), p.17091-17096
Main Authors: Marinari, Barbara, Moretti, Francesca, Botti, Elisabetta, Giustizieri, Maria Laura, Descargues, Pascal, Giunta, Alessandro, Stolfi, Carmine, Ballaro, Costanza, Papoutsaki, Marina, Alemà, Stefano, Monteleone, Giovanni, Chimenti, Sergio, Karin, Michael, Costanzo, Antonio
Format: Article
Language:English
Subjects:
Biological Sciences
Cell cycle
Cell growth
Cell lines
Cell nucleus
Down regulation
Epithelial cells
Keratinocytes
Skin
Tumor cell line
Tumors
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Summary:The transforming growth factor type β-1 (TGF-β) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IκB kinase α (IKKα) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKα in TGF-β signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKα and components of the TGF-β signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKα and the TGF-β signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKα to the nucleus, defective TGF-β-induced growth arrest was rescued by introduction of a constitutively nuclear IKKα variant. These results suggest that the tumor-suppressive activity of IKKα in stratified epithelia may be exerted in part via the TGF-β signaling pathway.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0809288105