年内第二篇Protein & Cell(IF=15.328)∣18新利体育 神经18新利备用网站 所曹聪课题组发现Gαi1蛋白上游关键基因
时间: 2022-10-20 作者: 浏览次数: 10

神经胶质母细胞瘤(GBM)等高级别胶质瘤是颅内常见肿瘤,致死致率高,预后极差。近年来对胶质瘤的治疗有所突破,但总的生存期仅能延长数月。一系列的促癌基因表达及功能异常和胶质瘤发生、发展密切相关。目前研究聚焦于探究新的关键信号通路和分子靶点。


18新利体育 神经18新利备用网站 所曹聪课题组多年来研究证实G蛋白抑制性α亚单位13Gαi1/3蛋白)是多个信号通路中的关键分子。多个细胞及生长因子刺激下,Gαi1/3蛋白和受体酪氨酸激酶(RTKs)等受体结合,并介导下游信号(PI3K-Akt-mTORErk-MAPK等)转导(Science Advances 2022[1], PNAS 2018[2], Protein & Cell2022a/b[3, 4]Science Signaling2009 [5]Oncogene2018, 2021 [6, 7]IJBS2022[8]Theranostics 20182021a/b[9-11]等论文)。课题组前期研究发现胶质瘤患者肿瘤组织标本中Gαi1/3表达显著上调;敲减、敲除Gαi1/3后可显著抑制胶质瘤细胞体外及在小鼠颅内生长(Oncogene2018[6]Theranostics 2021a[9])。但Gαi1/3蛋白表达调控的分子机制并不明确。


YME1LYME1 Like 1 ATPase)是AAA家族ATP酶的主要成员,位于线粒体内膜[12]YME1L对维持线粒体的形态、功能和可塑性至关重要[13]YME1L在线粒体内膜内组装成同源寡聚物,参与降解线粒体蛋白:包括脂质转运蛋白、线粒体内膜易位蛋白及OPA1等等;YME1L缺失导致线粒体分裂增加,线粒体碎片化;YME1L还参与细胞增殖并抑制细胞凋亡 [13]。但YME1L在人类胶质瘤中的表达和潜在功能仍不清楚。


20221019日,18新利体育 曹聪课题组在Protein & CellIF=15.328在线发表了题为“YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation研究论文,该研究揭示了YME1L通过促进Gαi1蛋白表达和下游Akt活化促胶质瘤细胞生长

结合TCGA数据库和患者组织标本发现,YME1L在胶质瘤组织中表达显著上调,且仅在线粒体中富集。在体外培养的人胶质瘤细胞中,运用病毒shRNA敲减或CRISPR/Cas9方法敲除YME1L显著抑制细胞的生长、增殖和迁移,并诱导细胞线粒体损伤和细胞凋亡;而运用病毒载体过表达YME1L则促胶质瘤细胞生长。机制研究发现,胶质瘤细胞中敲减及敲除YME1L后,Gαi1表达下调,下游Akt抑制;而过表达YME1L后,Gαi1表达水平增加,Akt激活。


Gαi1过表达或导入持续活化的AktcaAkt1)减轻YME1L敲除后抗胶质瘤细胞作用。在体研究发现,YME1L敲除后的人胶质瘤细胞在小鼠颅内生长显著抑制;肿瘤组织内Gαi1表达下调,Akt活化抑制。综上,YME1L通过介导Gαi1-Akt信号激活促胶质瘤细胞生长,该通路或是胶质瘤的一个重要新的治疗靶点。

论文受国家自然科学基金优秀青年基金和面上项目等资助。

原文链接:https://doi.org/10.1093/procel/pwac011

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