Abstract
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.
Highlights
The involvement of tumor suppressors in cancer pathogenesis has been extensively revised over the last years
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
BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion
Summary
The involvement of tumor suppressors in cancer pathogenesis has been extensively revised over the last years. Leukemia has always been considered as an unique disease because it was referred as a ‘single hit’ cancer [11] This interpretation is supported by the observation that BCRABL alone is sufficient to induce the rapid onset of a leukemic phenotype in several murine models, without the need of additional genetic lesions [12]. The revised model of tumor suppressor role in cancer suggests that BCR-ABL-mediated leukemogenesis could be associated with functional non genomic loss of tumor suppressors [2]. In this respect, PP2A and PTEN have already been described as BCR-ABL inhibited tumor suppressors [13,14,15,16,17,18]. We demonstrate that BCR-ABL promotes the formation of a ternary complex with IκBα and p53 in the cytoplasm causing loss of p53 tumor suppressive nuclear pool
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