Non genomic loss of function of tumor suppressors in CML: BCR-ABL promotes IκBα mediated p53 nuclear exclusion
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Sabrina Crivellaro1, Cristina Panuzzo1, Giovanna Carrà1, Alessandro Volpengo1, Francesca Crasto1, Enrico Gottardi1, Ubaldo Familiari2, Mauro Papotti2, Davide Torti1, Rocco Piazza3, Sara Redaelli3, Riccardo Taulli4, Angelo Guerrasio1, Giuseppe Saglio1, Alessandro Morotti1
1Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
2Division of Pathology, Department of Oncology, University of Turin at St Luigi Hospital, Torino, Italy
3Department of Health Sciences, University of Milano-Bicocca, Monza, Italy
4Department of Oncology, University of Turin, Turin, Italy
Alessandro Morotti, e-mail: [email protected]
Keywords: NF-κB, IκBα, chronic myeloid leukemia, p53, tumor suppressor
Received: February 05, 2015 Accepted: July 13, 2015 Published: July 23, 2015
Tumor suppressor function can be modulated by subtle variation of expression levels, proper cellular compartmentalization and post-translational modifications, such as phosphorylation, acetylation and sumoylation. The non-genomic loss of function of tumor suppressors offers a challenging therapeutic opportunity. The reactivation of a tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. The identification of mechanisms that affect tumor suppressor functions is therefore essential. In this work, we show that BCR-ABL promotes the accumulation of the NFKBIA gene product, IκBα, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/IκBα/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.
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