Non genomic loss of function of tumor suppressors in CML: BCR-ABL promotes IκBα mediated p53 nuclear exclusion
Non genomic loss of function of tumor suppressors in CML: BCR-ABL promotes IκBα mediated p53 nuclear exclusion
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DOI：
10.18632/oncotarget.4611
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发表时间：
2015-09-22
期刊：
影响因子：
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通讯作者：
Morotti, Alessandro
中科院分区：
文献类型：
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作者：
Crivellaro, Sabrina;Panuzzo, Cristina;Morotti, Alessandro
肿瘤抑制功能可以通过表达水平的微妙变化、适当的细胞区室化和翻译后修饰（例如磷酸化、乙酰化和苏酰化）来调节。肿瘤抑制因子的非基因组功能丧失提供了具有挑战性的治疗机会。肿瘤抑制因子的重新激活确实可以促进癌细胞的选择性凋亡，而不影响正常细胞。因此，确定影响肿瘤抑制功能的机制至关重要。在这项工作中，我们表明 BCR-ABL 通过物理相互作用和蛋白质的稳定性促进 NFKBIA 基因产物 I kappa B α 在细胞质中的积累。此外，BCR-ABL/I kappa B α 复合物充当有利于 p53 核排斥的支架蛋白。因此，我们鉴定了一种新型 BCR-ABL/I kappa B alpha/p53 网络，BCR-ABL 可通过该网络功能性地灭活关键的肿瘤抑制因子。
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, I kappa B alpha, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/I kappa B alpha complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/I kappa B alpha/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.