Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia.
Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia.
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DOI：
10.18632/oncotarget.21166
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发表时间：
2017-10-20
期刊：
影响因子：
--
通讯作者：
Castagnetti F
中科院分区：
文献类型：
--
作者：
Mancini M;Soverini S;Gugliotta G;Santucci MA;Rosti G;Cavo M;Martinelli G;Castagnetti F
CHIBBY1(CBY1)是一种进化保守的小分子蛋白，具有β-连环蛋白拮抗剂的作用。Cby1由C22orf2(22q13.1)编码，其对β-连环蛋白的拮抗作用涉及与β-连环蛋白的C端激活域直接相互作用，从而阻碍β-连环蛋白与Tcf/Lef转录因子的结合，从而抑制β-连环蛋白的转录激活。14-3-3支架蛋白(σ或ξ)，驱动CBY1核输出与β-连环蛋白形成稳定的三体复合体。编码CBY1的C22orf2基因与染色体22q11上的bcr断裂点比较接近，其与c-abl的易位和重排是慢性粒细胞白血病(CML)的致病事件，提示基因单倍体不足在CML的发生发展中可能起一定作用。我们发现CBY1下调与BCR-ABL1相关，由转录机制(启动子超甲基化)和转录后事件促进，通过SUMO化处理蛋白质朝向蛋白酶体依赖的降解。CBY1在克隆祖细胞中的表达减少，更重要的是，在白血病干细胞(LSC)中的表达减少，这取决于BCR-ABL1融合蛋白的酪氨酸激酶(TK)活性。因此，在伊马替尼(IM)和第二代TK抑制剂的诱导下，β-连环蛋白通过内质网(ER)应激相关的未折叠蛋白反应(UPR)激活和自噬等多个事件参与失活，最终导致细胞凋亡死亡。这些发现支持联合方案的优势，包括针对DNA表观遗传学和/或蛋白酶体的药物来根除bcr-abl1+造血。
Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression. We found CBY1 down-modulation associated with the BCR-ABL1, promoted by transcriptional mechanisms (promoter hyper-methylation) and post-transcriptional events, addressing the protein towards proteasome-dependent degradation through SUMOylation. CBY1 reduced expression in clonal progenitors and, more importantly, in leukemic stem cells (LSC), is contingent upon the tyrosine kinase (TK) activity of BCR-ABL1 fusion protein. Accordingly, its induction by Imatinib (IM) and second generation TK inhibitors contributes to β-catenin inactivation through multiple events encompassing the activation of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) and autophagy, eventually leading to apoptotic death. These findings support the advantage of combined regimens including drugs targeting DNA epigenetics and/or proteasome to eradicate the BCR-ABL1+ hematopoiesis.
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