Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
Int J Mol Sci. 2020 Jun 24;21(12):4465. doi: 10.3390/ijms21124465.
The Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved kinase complex coordinating cellular growth with nutritional conditions and growth factor signaling, and its activity is elevated in many cancer types. The use of TORC1 inhibitors as anticancer drugs is, however, limited by unwanted side-effects and development of resistance. We therefore attempted to identify limiting modulators or downstream effectors of TORC1 that could serve as therapeutic targets. epithelial tissues that lack the tumor suppressor Pten hyperproliferate upon nutrient restriction in a TORC1-dependent manner. We probed candidates of the TORC1 signaling network for factors limiting the overgrowth of mutant tissues. The serine/arginine-rich splicing factor 2 (SF2) was identified as the most limiting factor: knockdown drives mutant cells into apoptosis, while not affecting control tissue. SF2 acts downstream of or in parallel to TORC1 but is not required for the activation of the TORC1 target S6K. Transcriptomics analysis revealed transcripts with alternatively used exons regulated by SF2 in the tumor context, including . SF2 may therefore represent a highly specific therapeutic target for tumors with hyperactive TORC1 signaling.
雷帕霉素靶蛋白复合物 1（TORC1）是一种进化上保守的激酶复合物，协调细胞生长与营养条件和生长因子信号，其活性在许多癌症类型中升高。然而，由于不良反应和耐药性的发展，TORC1 抑制剂作为抗癌药物的应用受到限制。因此，我们试图确定 TORC1 的限制调节剂或下游效应物，它们可以作为治疗靶点。在缺乏肿瘤抑制因子 Pten 的上皮组织中，营养限制以 TORC1 依赖的方式导致过度增殖。我们探测了 TORC1 信号网络的候选因子，以寻找限制突变组织过度生长的因素。丝氨酸/精氨酸丰富的剪接因子 2（SF2）被鉴定为最具限制作用的因子：SF2 敲低会导致 突变细胞凋亡，而不影响对照组织。SF2 作用于 TORC1 的下游或平行，但不是 TORC1 靶标 S6K 的激活所必需的。转录组学分析显示，在肿瘤环境中，SF2 调节具有不同外显子使用的转录本，包括 。SF2 因此可能代表具有过度活跃的 TORC1 信号的肿瘤的高度特异性治疗靶点。
