Department of Experimental Diagnostic and Specialty Medicine - DIMES - Institute of Hematology L and A Seràgnoli, University of Bologna-Medical School, Italy.
Cell Signal. 2013 Sep;25(9):1820-7. doi: 10.1016/j.cellsig.2013.05.019. Epub 2013 May 24.
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL fusion protein. However, the phenotype of leukemic stem cells (LSC) is sustained by β catenin rather than by the BCR-ABL TK. β catenin activity in CML is contingent upon its stabilization proceeding from the BCR-ABL-induced phosphorylation at critical residues for interaction with the Adenomatous polyposis coli (APC)/Axin/glycogen synthase kinase 3 (GSK3) destruction complex or GSK3 inactivating mutations. Here we studied the impact of β catenin antagonist Chibby (CBY) on β catenin signaling in BCR-ABL1+ cells. CBY is a small conserved protein which interacts with β catenin and impairs β catenin-mediated transcriptional activation through two distinct molecular mechanisms: 1) competition with T cell factor (TCF) or lymphoid enhancer factor (LEF) for β catenin binding; and 2) nuclear export of β catenin via interaction with 14-3-3. We found that its enforced expression in K562 cell line promoted β catenin cytoplasmic translocation resulting in inhibition of target gene transcription. Moreover, cytoplasmic accumulation of β catenin activated the endoplasmic reticulum (ER) stress-associated pathway known as unfolded protein response (UPR). CBY-driven cytoplasmic accumulation of β catenin is also a component of BCR-ABL1+ cell response to the TK inhibitor Imatinib (IM). It evoked the UPR activation leading to the induction of BCL2-interacting mediator of cell death (BIM) by UPR sensors. BIM, in turn, contributed to the execution phase of apoptosis in the activation of ER resident caspase 12 and mobilization of Ca(2+) stores.
慢性髓性白血病（CML）是一种骨髓增生性疾病，由 BCR-ABL 融合蛋白的组成性酪氨酸激酶（TK）活性引起。然而，白血病干细胞（LSC）的表型是由β连环蛋白维持的，而不是由 BCR-ABL TK 维持的。CML 中的β连环蛋白活性依赖于其从 BCR-ABL 诱导的关键残基磷酸化稳定，这些关键残基对于与腺瘤性结肠息肉（APC）/轴蛋白/糖原合成酶激酶 3（GSK3）降解复合物或 GSK3 失活突变的相互作用至关重要。在这里，我们研究了β连环蛋白拮抗剂 Chibby（CBY）对 BCR-ABL1+细胞中β连环蛋白信号的影响。CBY 是一种小的保守蛋白，与β连环蛋白相互作用，并通过两种不同的分子机制损害β连环蛋白介导的转录激活：1）与 T 细胞因子（TCF）或淋巴增强因子（LEF）竞争β连环蛋白结合；2）通过与 14-3-3 相互作用将β连环蛋白核输出。我们发现，在 K562 细胞系中强制表达 CBY 可促进β连环蛋白细胞质易位，从而抑制靶基因转录。此外，β连环蛋白的细胞质积累激活了已知的未折叠蛋白反应（UPR）内质网（ER）应激相关途径。CBY 驱动的β连环蛋白细胞质积累也是 BCR-ABL1+细胞对 TK 抑制剂伊马替尼（IM）反应的一部分。它引发 UPR 激活，导致 UPR 传感器诱导 BCL2 相互作用介导线粒体凋亡（BIM）。反过来，BIM 通过激活内质网驻留半胱天冬酶 12 和动员钙库，有助于 ER 凋亡执行阶段。
