Since JUN was discovered, almost 20 years ago, it has been shown to regulate proliferation and survival in both normal tissues and tumours. It seems to be particularly important for hepatocytes, which has led to the hypothesis that it is also involved in the development of hepatic carcinomas. Erwin Wagner and colleagues have investigated this in mice, and show that Jun promotes tumorigenesis by switching off p53, which, in turn, switches off death.

A conditional allele system was used to specifically delete Jun in hepatocytes initially at around birth, and the mice were then subjected to a chemical carcinogenesis protocol to induce liver tumours. The control mice had large tumours by the age of 6 months and 60% had died due to liver failure by 18 months. The liver-specific JunΔ mice, on the other hand, had fewer and smaller tumours, and only 10% had died by 18 months, indicating that the deletion of Jun can suppress liver tumour formation. But does this suppression occur because of decreased proliferation or increased apoptosis?

The authors determined the rate of proliferation and apoptosis in control and JunΔ tumours using cellular markers for each — Ki67 and TUNEL, respectively — to investigate this. Although the number of proliferating cells was similar in both tumour types, the number of apoptotic cells was greatly increased in JunΔ tumours, indicating that Jun acts as a survival factor in liver tumour cells.

To further analyse the requirement for this survival function of Jun, the authors deleted it at different stages of hepatic tumour development. Tumour formation was repressed to a similar extent regardless of whether Jun was deleted before or after tumour initiation, and the survival function also seems to be independent of tumour promotion. The activating amino-terminal phosphorylation of Jun was also not required for this activity, as mutation of these sites to alanine did not impair tumour formation. Interestingly, deleting Jun 6 months after tumour initiation did not then cause tumour regression — the tumours had become independent of Jun. Jun therefore facilitates tumour development by inhibiting apoptosis at an early stage, between initiation and progression.

So how does Jun activity repress apoptosis? The expression levels of several Bcl2 family members and death receptors were not altered in JunΔ hepatocytes compared with control hepatocytes, but the response to the TNF-α death ligand was. Deletion of Jun seems to sensitize hepatocytes to TNF-α-induced apoptosis by increasing the activity of the JNK and p38 stress kinases. These kinases have been shown to activate p53, which indicates a mechanism for the increased apoptosis in JunΔ tumours. Indeed, hepatocytes that were deficient for both Jun and Trp53 had a restored resistance to induced TNFα-apoptosis.

But is the same true in tumours? Biopsies from both control and JunΔ liver tumours confirmed that p53 levels were increased in the absence of Jun, and that this corresponded with an increase in expression of a pro-apoptotic target of p53, Noxa.

So, in hepatic tumour development, Jun seems to promote tumorigenesis by antagonizing the pro-apoptotic function of p53. The design of Jun inhibitors might therefore prove a useful therapeutic strategy for this cancer type.