Missing link found in cancer gene pathway

08 April 2015

Microscopic sections of mouse lung tumour with normal levels of Trim7 (left) and increased levels of Trim7 (right). There are more dividing cells (stained brown) in the tumour with increased levels of Trim7, so these tumours grow faster.

Image: Microscopic sections of mouse lung tumour with normal levels of Trim7 (left) and increased levels of Trim7 (right). There are more dividing cells (stained brown) in the tumour with increased levels of Trim7, so these tumours grow faster.

Researchers have discovered the missing link in a pathway that could be targeted to block the effects of Ras, a commonly mutated gene that drives cancer development.

Dr Axel Behrens, of the Francis Crick Institute (currently based at Lincoln's Inn Fields), explained: "Ras is one of the most commonly mutated genes driving cancer development. However, Ras itself is notorious for being 'undruggable', meaning it can't be blocked by any currently available drug.

"We therefore need to understand the complex signalling network activated by Ras in order to tackle cancers that are driven by this gene."

One of Ras's many effects is to switch on a set of genes involved in cell growth by activating a factor known as AP-1. Although researchers have known that Ras activates AP-1 for over 25 years, the molecular connection between them has been a long-standing mystery.

Five years ago the team identified some of the key players involved, but there were gaps in the pathway - indicating that something was still missing. Now they have found the final piece of the puzzle - an enzyme called Trim7.

The scientists showed that Trim7 is a type of enzyme called a ubiquitin ligase - it controls the stability of other proteins. They were able to pinpoint exactly how Ras signalling activates Trim7 and found that, in fact, Trim7 can be connected back via a chain of enzymes to Ras, and connected forward to AP-1 activation - it completes the missing link between the two.

The team used genetic techniques to increase and decrease the amount of Trim7 in lung cancer cells. They found that increasing the amount of Trim7 increased the growth of lung tumours with mutated Ras. Decreasing the amount of Trim7 reduced the growth of lung cancer cells with mutated Ras - suggesting that mutant Ras relies on Trim7 to maximise its tumour-driving effects.

Dr Behrens said: "Our data suggest that reducing the amount of Trim7 could slow the growth of lung tumours that have mutations in the Ras gene.

"Although drugs targeting Trim7 are not available, it is possible that targeting the enzymes close to it in the chain will also be able to interfere with this pathway and slow tumour growth. It is also likely that Trim7 is involved in other types of cancer with a mutated Ras gene.

"If in the future we find a drug that interferes with the Trim7 pathway, we might be able to block some of the effects of mutant Ras in several different tumour types."

The paper, The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling, is published in Nature Communications.

  • Scientists at the Francis Crick Institute have discovered the missing link in a growth pathway involving Ras, a gene that is commonly mutated in cancer. They hope the findings may lead to ways to block the effects of the gene to slow cancer growth.
  • The Ras family of proteins are signalling proteins that switch on genes involved in cell growth and survival. The three human versions of Ras are some of the most common cancer-causing genes in humans.