School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
Cell Biol Toxicol. 2023 Aug;39(4):1795-1814. doi: 10.1007/s10565-022-09784-4. Epub 2022 Dec 19.
SETβ is the predominant isoform of oncoprotein SE translocation (SET) in various breast cancer cell lines. Interactome-transcriptome analysis has shown that SETβ is intimately associated with cellular stress response. Among various exogenous stimuli, formaldehyde (FA) causes distinct biological effects in a dose-dependent manner. In response to FA at different concentrations, SET dynamically shuttles between the nucleus and cytoplasm, performing diverse biofunctions to restore homeostasis. At a low concentration, FA acts as an epidermal growth factor (EGF) and activates the HER2 receptor and downstream signaling pathways in HER2 breast cancer cells, resulting in enhanced cell proliferation. Nucleocytoplasmic transport of SETβ is controlled by the PI3K/PKCα/CK2α axis and depletion or blockade of the transport of SETβ suppresses EGF-induced activation of AKT and ERK. SETβ also inhibits not only stress-induced activation of p38 MAPK signaling pathway, but also assembly of stress granules by hindering formation of the G3BP1-RNA complex. Our findings suggest that SET functions as an important regulator which modulates cellular stress signaling pathways dynamically.
SETβ 是各种乳腺癌细胞系中致癌蛋白 SET 易位（SET）的主要异构体。互作组转录组分析表明，SETβ 与细胞应激反应密切相关。在各种外源性刺激物中，甲醛（FA）以剂量依赖的方式引起明显的生物学效应。在不同浓度的 FA 作用下，SET 会在核质之间动态穿梭，发挥多种生物功能以恢复内稳态。在低浓度时，FA 作为表皮生长因子（EGF）激活 HER2 乳腺癌细胞中的 HER2 受体和下游信号通路，导致细胞增殖增强。SETβ 的核质转运由 PI3K/PKCα/CK2α 轴控制，SETβ 转运的耗竭或阻断抑制了 EGF 诱导的 AKT 和 ERK 的激活。SETβ 不仅抑制应激诱导的 p38 MAPK 信号通路的激活，还通过阻碍 G3BP1-RNA 复合物的形成来抑制应激颗粒的组装。我们的研究结果表明，SET 作为一种重要的调节剂，动态调节细胞应激信号通路。
