Adult Stem Cell Laboratory.
Experimental Histopathology, and.
JCI Insight. 2021 Jul 8;6(13):e124985. doi: 10.1172/jci.insight.124985.
The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.
AP-1 转录因子 c-Jun 在许多组织中是 Ras 驱动的肿瘤发生所必需的，被认为是经典的原癌基因。为了确定 c-Jun 在 K-RasG12D 诱导的肺腺癌小鼠模型中的需求，我们在成年肺部中诱导性地缺失了 c-Jun。令人惊讶的是，我们发现 c-Jun 的失活或其 JNK 磷酸化位点的突变实际上增加了肺肿瘤负担。在机制上，我们发现 Jun 家族成员 JunD 的蛋白水平在没有 c-Jun 的情况下增加。在缺乏 c-Jun 的细胞中，JunD 的磷酸化增加，并且表达显性激活的 JNKK2-JNK1 转基因进一步增加了肺肿瘤的形成。引人注目的是，JunD 的缺失完全消除了 Ras 驱动的肺肿瘤发生。这项工作确定了 JunD 而不是 c-Jun 是 JNK 信号和 Ras 诱导的肺癌所需致癌基因的关键底物。
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