Tumour suppressor function for the AP-1 transcription factor c-Jun in Ras-induced lung cancer

Ras信号通路的异常激活通常发生在人肺腺癌中，其中33%的病例携带K-Ras突变，因此迫切需要靶向Ras信号通路的治疗。由于直接靶向致癌Ras已被证明极具挑战性，因此详细了解Ras下游通路对于Ras驱动的肺癌的靶向治疗至关重要，Ras驱动的肺癌是一种通常对当前治疗反应不佳的肿瘤类型。在其许多输出中，致癌Ras信号刺激AP-1转录激活因子家族，AP-1转录激活因子家族反过来控制参与增殖、迁移和凋亡的大量基因。特别是，AP-1成员c-Jun长期以来一直被认为是许多组织如皮肤和肝脏中Ras介导的肿瘤发生的重要组成部分。令人惊讶的是，由宿主Behrens实验室进行的最初小鼠遗传分析揭示了c-Jun在K-Ras驱动的肺癌中的肿瘤抑制功能。这里提出的项目旨在详细研究c-Jun意外的肿瘤抑制功能的机制。首先，c-Jun N-末端磷酸化在其肿瘤抑制功能中的相关性将通过引入突变的c-将丝氨酸63和73突变为丙氨酸的Jun等位基因（c-JunAA）用于K-Ras诱导的小鼠肺癌模型。第二，其他Jun蛋白JunD和JunB在K-Ras诱导的肺肿瘤发生中的作用将通过将功能丧失等位基因与致癌K-Ras结合来确定。第三，将检查由不同Jun蛋白调节的基因表达程序和K-Ras诱导的肺肿瘤细胞中每个Jun的DNA结合谱，并对特定靶基因进行功能验证。预计该项目将阐明c-Jun相对于JunD和JunB在肺肿瘤发生中的功能的重要差异，并确定其蛋白质产物可能是治疗上易处理的重要肿瘤促进基因。

Abnormal activation of the Ras signalling pathway commonly occurs in human lung adenocarcinomas, with 33% of cases harbouring mutations in K-Ras, therefore the therapies targeting Ras signalling are urgently needed. Since direct targeting of oncogenic Ras has proved extremely challenging, a detailed understanding of Ras downstream pathways is critical to enable targeted therapy for Ras-driven lung cancer, a tumour type that often responds poorly to current treatments. Among its many outputs, oncogenic Ras signalling stimulates the AP-1 transcriptional activator family, which in turn controls a vast suite of genes involved in proliferation, migration and apoptosis. In particular, the AP-1 member c-Jun has long been known as an important component of Ras-mediated tumourigenesis in many tissues such as the skin and the liver. Surprisingly, the initial mouse genetic analysis by the host Behrens laboratory revealed a tumour suppressor function of c-Jun in K-Ras-driven lung cancer.The project proposed here aims to investigate in detail the mechanism underlying the unexpected tumour suppressor function of c-Jun. First, the relevance of c-Jun N-terminal phosphorylation in its tumour suppressor function will be examined by introducing mutant c-Jun alleles with serines 63 and 73 mutated to alanines (c-JunAA) to a K-Ras-induced mouse lung cancer model. Second, the role of the other Jun proteins JunD and JunB in K-Ras-induced lung tumourigenesis will be determined by combining loss-of-function alleles with the oncogenic K-Ras. Third, the gene expression programmes regulated by different Jun proteins and the DNA binding profiles for each Jun in K-Ras-induced lung tumour cells will be examined and specific target genes will be functionally validated. It is expected that the project will elucidate an important difference in the function of c-Jun relative to JunD and JunB in lung tumourigenesis, and identify important tumour-promoting genes whose protein products may be therapeutically tractable.