BioWorld International Correspondent
LONDON - A gene known to play a role in cancer development could hold the key to new treatments for nerve injury.
The gene, which encodes a protein called c-Jun, is present at high levels in certain types of tumors - but damaged nerve cells also produce it in large quantities.
Now a new study has shown that injured nerve cells that are stopped from making c-Jun also are unable to regenerate, suggesting that c-Jun is the master regulator of nerve repair.
Axel Behrens, principal investigator at the Cancer Research UK Mammalian Genetics Laboratory, told BioWorld International: "This study shows how important it is for scientists not to have tunnel vision, because many systems are interwoven and many molecules have dual functions. C-Jun is clearly important for both neuronal regeneration and for tumor development. I am very excited about this finding because it is possible that we may be able to apply much of our work on regulators of c-Jun in tumors to help develop new therapies for nerve repair."
Behrens, together with collaborators led by Gennadij Raivich at the Perinatal Brain Repair Group at University College London, hopes to have results within six months from further studies to establish whether the latest finding can be harnessed to stimulate nerves that normally do not regenerate after injury to do so.
The work is published in the July 8, 2004, issue of Neuron in a paper titled "The AP-1 Transcription Factor c-Jun is Required for Efficient Axonal Regeneration."
C-Jun is found at high levels in different forms of cancer, including skin, liver and Hodgkin's lymphoma. In addition, when the axons of some types of nerve cells are severed, the cell bodies also produce large amounts of c-Jun, which is sustained over a long period.
Behrens explained: "The interesting aspect of this is that there is long-lasting c-Jun up-regulation and induction in those nerves that can regenerate, whereas in nerves that do not regenerate, such as the spinal cord, there is only transient production of c-Jun."
Behrens, Raivich and their colleagues decided to investigate what would happen to nerve cells' ability to regenerate if c-Jun were absent. Knockout mice lacking the gene for c-Jun die as embryos, so the team used transgenic mice developed in Behrens' lab that lacked c-Jun only in the central nervous system. Tests had shown that those mice were neurologically comparable to wild-type mice.
Transection of the facial nerve of mice results in a loss of movement with the eye, eyelid, lip and whisker hairs on the affected side. In wild-type mice, the nerve regenerates and movement is partially restored within four to five weeks, with regeneration complete by 3.5 months. However, in the c-Jun-deficient mice, the amount of regeneration was reduced by 70 percent to 80 percent, showing that c-Jun is required for normal regeneration.
"We now want to know whether c-Jun is not only required, but whether giving neurons c-Jun is sufficient for them to acquire the capacity to regenerate," Behrens said. "We are now trying to overproduce c-Jun in spinal cord neurons to find out whether we can make neurons regenerate that normally do not regenerate. If this works, it would be of enormous clinical significance."
There is another interesting twist to the story. Two months ago, the Cancer Research UK team published a paper in Science describing a protein called Fbw7 that destroys c-Jun.
"We know that this protein is a tumor suppressor, and that it is mutated in tumors," Behrens said. "This is probably one reason why there is so much c-Jun in tumors - because the molecule that normally degrades it is mutated. So it will be interesting to see whether this protein is also responsible for the absence of c-Jun in non-regenerating neurons. It could be an interesting drug target. If we could inactivate it, our model suggests that the result would be overproduction of c-Jun, and that this would facilitate nerve regeneration."
Behrens agreed that there could be a risk that such treatment could be oncogenic, but said the risk would be small. Neurons are post-mitotic cells, he pointed out, and, in any case, most tumors represent the culmination of many mutations over time. Furthermore, treatment probably would need to be given for only a short period.