Vivanco Igor, Palaskas Nicolaos, Tran Chris, Finn Stephen P, Getz Gad, Kennedy Norman J, Jiao Jing, Rose Joshua, Xie Wanling, Loda Massimo, Golub Todd, Mellinghoff Ingo K, Davis Roger J, Wu Hong, Sawyers Charles L
Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Cancer Cell. 2007 Jun;11(6):555-69. doi: 10.1016/j.ccr.2007.04.021.
Although most oncogenic phenotypes of PTEN loss are attributed to AKT activation, AKT alone is not sufficient to induce all of the biological activities associated with PTEN inactivation. We searched for additional PTEN-regulated pathways through gene set enrichment analysis (GSEA) and identified genes associated with JNK activation. PTEN null cells exhibit higher JNK activity, and genetic studies demonstrate that JNK functions parallel to and independently of AKT. Furthermore, PTEN deficiency sensitizes cells to JNK inhibition and negative feedback regulation of PI3K was impaired in PTEN null cells. Akt and JNK activation are highly correlated in human prostate cancer. These findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.
尽管PTEN缺失的大多数致癌表型都归因于AKT激活，但仅AKT不足以诱导所有与PTEN失活相关的生物学活性。我们通过基因集富集分析（GSEA）寻找其他PTEN调控的通路，并鉴定了与JNK激活相关的基因。PTEN缺失的细胞表现出更高的JNK活性，遗传学研究表明JNK与AKT平行且独立发挥作用。此外，PTEN缺陷使细胞对JNK抑制敏感，并且PTEN缺失的细胞中PI3K的负反馈调节受损。在人类前列腺癌中，Akt和JNK激活高度相关。这些发现表明JNK参与PI3K驱动的癌症，并证明了GSEA在使用基因定义系统鉴定功能通路方面的实用性。
