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

• Applicant: Linxiang Lan, Ph.D.
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology ; Biochemistry
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 312012787

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.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Axel Behrens