CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2.
CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2.
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DOI：
10.1038/cddis.2014.276
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发表时间：
2014-07-17
影响因子：
9
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中科院分区：
文献类型：
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p53-2凋亡刺激蛋白（Apoptosis-stimulatingproteinofp 53 -2，ASPP 2）通过与p53或p73结合促进促凋亡基因的表达而诱导细胞凋亡，但ASPP 2诱导肝癌细胞凋亡的确切机制尚不清楚。在这里，我们表明，瞬时过表达的ASPP 2诱导肝癌细胞自噬凋亡，促进p53或p73非依赖性C/EBP同源蛋白（CHOP）的表达。CHOP表达降低Bcl-2的表达;这种变化从细胞质Bcl-2-Beclin-1复合物中释放Beclin-1，并使其启动自噬。然而，Beclin-1的瞬时过表达可以诱导自噬而不是凋亡。我们的研究结果表明，ASPP 2诱导损伤调节自噬调节剂（DRAM）的表达，这是与游离Beclin-1合作诱导自噬细胞凋亡的另一个关键因素。CHOP对Bcl-2在细胞核中的移位和隔离的影响，这需要Bcl-2与ASPP 2的结合，对于ASPP 2诱导的自噬性凋亡也是至关重要的。虽然核ASPP 2-Bcl-2复合物的作用还不清楚，但我们的研究结果表明，核ASPP 2可以通过以CHOP依赖的方式与Bcl-2结合来阻止剩余的Bcl-2易位到细胞质中，并且这种作用也有助于Beclin-1启动的自噬。因此，CHOP通过降低Bcl-2表达和维持核ASPP 2-Bcl-2复合物来介导ASPP 2诱导的自噬性细胞凋亡是至关重要的。我们的研究结果确定了ASPP 2过表达诱导自噬细胞凋亡的机制，为促进自噬治疗肝细胞癌开辟了新的途径。
Apoptosis-stimulating protein of p53-2 (ASPP2) induces apoptosis by promoting the expression of pro-apoptotic genes via binding to p53 or p73; however, the exact mechanisms by which ASPP2 induces apoptotic death in hepatoma cells are still unclear. Here, we show that the transient overexpression of ASPP2 induces autophagic apoptosis in hepatoma cells by promoting p53- or p73-independent C/EBP homologous protein (CHOP) expression. CHOP expression decreases the expression of Bcl-2; this change releases Beclin-1 from cytoplasmic Bcl-2-Beclin-1 complexes and allows it to initiate autophagy. However, transient overexpression of Beclin-1 can induce autophagy but not apoptosis. Our results show that ASPP2 induces the expression of damage-regulated autophagy modulator (DRAM), another critical factor that cooperates with free Beclin-1 to induce autophagic apoptosis. The effect of CHOP on the translocation and sequestration of Bcl-2 in the nucleus, which requires the binding of Bcl-2 to ASPP2, is also critical for ASPP2-induced autophagic apoptosis. Although the role of nuclear ASPP2–Bcl-2 complexes is still unclear, our results suggest that nuclear ASPP2 can prevent the translocation of the remaining Bcl-2 to the cytoplasm by binding to Bcl-2 in a CHOP-dependent manner, and this effect also contributes to Beclin-1-initiated autophagy. Thus, CHOP is critical for mediating ASPP2-induced autophagic apoptosis by decreasing Bcl-2 expression and maintaining nuclear ASPP2–Bcl-2 complexes. Our results, which define a mechanism whereby ASPP2 overexpression induces autophagic apoptosis, open a new avenue for promoting autophagy in treatments to cure hepatocellular carcinoma.
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DOI：
10.1111/liv.12238
发表时间：
2013-11
期刊：
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影响因子：
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