Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1.
Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1.
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白藜芦醇具有很强的抗癌活性，表现为通过激活p53诱导细胞凋亡。然而，白藜芦醇诱导的p53激活的分子机制和直接靶点仍然难以捉摸。在这里，Ras-GTPase激活蛋白SH 3结构域结合蛋白1（G3 BP 1）被确定为白藜芦醇的潜在靶点，并且使用白藜芦醇（RSVL）缀合的Sepharose 4 B珠的体外结合试验结果证实了它们的直接结合。G3 BP 1的耗尽显著减少白藜芦醇诱导的p53表达和凋亡。我们还发现G3 BP 1通过与p53的去泛素化酶泛素特异性蛋白酶10（USP 10）相互作用来负调控p53的表达。通过G3 BP 1干扰破坏p53与USP 10的相互作用导致p53去泛素化的抑制。另一方面，白藜芦醇直接与G3 BP 1结合并阻止G3 BP 1/USP 10相互作用，导致USP 10介导的p53去泛素化增强，从而增加p53表达。这些发现揭示了白藜芦醇通过直接靶向G3 BP 1诱导p53活化和白藜芦醇诱导细胞凋亡的新机制。
Resveratrol possesses a strong anticancer activity exhibited as the induction of apoptosis through p53 activation. However, the molecular mechanism and direct target(s) of resveratrol-induced p53 activation remain elusive. Here, the Ras-GTPase activating protein SH3 domain binding protein 1 (G3BP1) was identified as a potential target of resveratrol, and in vitro binding assay results using resveratrol (RSVL)-conjugated Sepharose 4B beads confirmed their direct binding. Depletion of G3BP1 significantly diminishes resveratrol-induced p53 expression and apoptosis. We also found that G3BP1 negatively regulates p53 expression by interacting with ubiquitin-specific protease 10 (USP10), a deubiquitinating enzyme of p53. Disruption of the interaction of p53 with USP10 by G3BP1 interference leads to suppression of p53 deubiquitination. Resveratrol, on the other hand, directly binds to G3BP1 and prevents the G3BP1/USP10 interaction, resulting in enhanced USP10-mediated deubiquitination of p53 and consequently increased p53 expression. These findings disclose a novel mechanism of resveratrol-induced p53 activation and resveratrol-induced apoptosis by direct targeting of G3BP1.
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