The JNK and Hippo pathways regulate an overlapping transcriptome to control neoplastic tissue growth
Authors: Katrina Mitchell 1,2; Joseph Vissers 4; Kieran Harvey 1,2,3
Affiliations: 1) Peter MacCallum Cancer Centre, Melbourne, Australia; 2) Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia; 3) Depart of Anatomy and Developmental Biology, Monash University, Australia; 4) Department of Clinical Pathology, University of Melbourne, Australia
Keywords: o. tissue growth and remodeling; g. Hippo
The final size of an organ is determined by both organ-extrinsic and organ-intrinsic factors, which can adapt to changes in environmental conditions and tissue damage. Homeostatic mechanisms eliminate damaged or abnormal cells to prevent tumour growth, which in turn facilitates compensatory proliferation to maintain organ size. In growing Drosophila melanogaster epithelial tissues, cells with disrupted apical basal polarity are eliminated by neighbouring wild type cells through cell competition. The JNK pathway limits the growth and viability of neoplastic cells and has been reported to do this by suppressing the key Hippo pathway transcriptional regulatory protein Yorkie. Using targeted DamID and transcriptomics, we have identified target genes of the JNK and Hippo pathway transcription factors and found that these pathways act in parallel to regulate overlapping target genes. Yorkie activates the transcription of genes that promote cell proliferation and survival, whilst the JNK pathway transcription factors Jun and Fos repress transcription of these genes specifically in neoplastic cells. Additionally, we have identified a co-repressor that Jun/Fos cooperates with to prevent the uncontrolled growth of neoplastic tumours. These findings shed new light on organ size control, tissue damage and tumour suppression.