Open AccessThe tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway
Author(s) -
Barbara Marinari,
Francesca Moretti,
Elisabetta Botti,
Maria Laura Giustizieri,
Pascal Descargues,
Alessandro Giunta,
Carmine Stolfi,
Costanza Ballarò,
Marina Papoutsaki,
Stefano Alemá,
Giovanni Monteleone,
Sergio Chimenti,
Michael Karin,
Antonio Costanzo
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0809288105
Subject(s) - transforming growth factor beta , cancer research , tgf beta signaling pathway , signal transduction , transforming growth factor , biology , carcinogenesis , suppressor , microbiology and biotechnology , cancer , genetics
The transforming growth factor type beta-1 (TGF-beta) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IkappaB kinase alpha (IKKalpha) 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 IKKalpha in TGF-beta signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKalpha and components of the TGF-beta signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKalpha and the TGF-beta signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKalpha to the nucleus, defective TGF-beta-induced growth arrest was rescued by introduction of a constitutively nuclear IKKalpha variant. These results suggest that the tumor-suppressive activity of IKKalpha in stratified epithelia may be exerted in part via the TGF-beta signaling pathway.