JUN steps in

The activity of the transcription factor c-JUN is increased in several human cancers. In their Nature paper, Axel Behrens and colleagues now show that c-JUN is part of a transcriptional complex that is central to the development of colorectal cancer.

Loss of the adenomatous polyposis coli gene ( APC ) predisposes individuals to an increased risk of developing colorectal cancer. APC binds to axin and the glycogen synthase kinase GSK3β, and this complex phosphorylates the transcription regulator β-catenin, marking it for ubiquitylation and degradation. Only when WNT binds to its receptor, Frizzled, is this complex disrupted, allowing β-catenin to accumulate in the nucleus. Here it interacts with members of the transcription factor family T-cell factor/lymphoid enhancing factor (TCF/LEF). WNT signalling can also affect other pathways including activation of the c-JUN N-terminal kinases (JNKs) that activate c-JUN by phosphorylating its N-terminus. The authors had previously identified factors that bind specifically to phosphorylated c-JUN and one of these was TCF4. As TCF4 can also interact with β-catenin, the authors investigated the interaction of TCF4 with both β-catenin and c-JUN. They found that the interaction of TCF4 with c-JUN is dependent on the phosphorylation of two N-terminal serines (Ser63 and Ser73) in c-JUN, and that TCF4 can bind both β-catenin and c-JUN simultaneously.

c-JUN autoregulates its own transcription by binding to two proximal sites in its own promoter. Interestingly, c-JUN also has a TCF consensus binding sequence upstream of these sites. The authors therefore investigated the regulation of c-JUN transcription, the efficiency of which, they found, was dependent on JNK and required an intact c-JUN–TCF4–β-catenin complex.

To study the biological consequences of the c-JUN–TCF4–β-catenin complex, the authors used the Apc^Min/+ mouse, which lacks one functional Apc allele and develops multiple intestinal neoplasias because of the subsequent loss of the wild-type allele. They bred these mice with Jun^AA mice, in which Ser63 and Ser73 of c-JUN are changed to alanines and so cannot bind TCF4. Apc^Min/+c-Jun^+/+ and Apc^Min/+Jun^AA/+ mice all developed intestinal neoplasia, but Apc^Min/+Jun^AA/AA homozygotes developed intestinal cancer at a significantly slower rate. The tumours in these animals were also smaller and less frequent. This was caused by the significantly decreased proliferative index of the Apc^Min/+Jun^AA/AA homozygote tumour cells.

What happens if c-Jun is deleted from the intestinal cells in Apc^Min/+ mice? These animals did not develop intestinal neoplasia, but instead had multiple cystic structures throughout the gut. The cysts showed accumulation of β-catenin, due to APC loss, as did the tumours in c-Jun wild-type Apc^Min/+ mice. The authors concluded that in the absence of c-Jun, activation of the β-catenin pathway is incapable of triggering tumour development, but instead causes formation of benign cysts.

As Jun^AA homozygous mice have normal development and life span, inhibition of the phospho-c-JUN–TCF4 interaction could be a possible target for the treatment of intestinal cancer.