HSCS-RSZ · Regulation of hematopoietic stem cells commitment by JNK signalling pathway

Final Activity Report Summary - HSCS-RSZ (Regulation of Hematopoietic Stem Cells commitment by JNK signalling pathway)

Colorectal cancer is among the most prevalent forms of cancer worldwide. Activation of Wnt signalling through loss of function of the tumour-suppressor gene APC (adenomatous polyposis coli) is associated with the development of both human and murine intestine neoplasia. We have found that phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumourigenesis by integrating JNK and APC/ß-catenin, two distinct pathways activated by WNT signalling. The E3 ubiquitin ligase Fbw7 is a tumour suppressor commonly mutated in a wide spectrum of human cancers, including colon cancer. We have shown that Fbw7 mediates the degradation of phosphorylated c-Jun. We generated mice lacking Fbw7 in the gut, which showed drastically impaired differentiation into secretory lineage cells and hyperproliferation of progenitor/stem cells accompanied by increased levels of phosphorylated c-Jun and Notch-1. Thus Fbw7 controls intestinal stem differentiation and homeostasis. Moreover, we generated a mouse model allowing the inducible activation of JNK signalling in mice. Increased JNK function in the gut resulted in c-Jun activation and concomitant hyperproliferation of crypts cells. Interestingly, TCF4 was identified as a new transcriptional target of JNK signalling. These data support the notion of bidirectional regulation between JNK and Wnt/ß-catenin signalling. As our works highlights JNK as a therapeutic target for intestinal tumourigenesis, together with CRT we have entered a collaboration with a pharmaceutical company and licensed novel JNK inhibitors. Some of these compounds have shown promising activity towards human colon cancer cells in vitro, and are currently undergoing pre-clinical testing using in vivo models of colon cancer.

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