Most of your scientific career has been devoted to studying the protein ubiquitin. What is it, and why is it so important?

Ubiquitin is a fairly innocuous-looking protein. It's very small, as proteins go, containing 76 amino acids – an amino acid being the basic building block of a protein. It doesn't seem to have any enzyme activity of its own, but it is very important because the cell uses it as a mechanism to mark or signal other proteins for destruction in the cell. The cell takes this little ubiquitin molecule and attaches several moieties of it (several units of ubiquitin) to a protein; that targets the protein for degradation at a large proteolytic complex inside the cell, called the proteasome. That is a collection of proteases that specifically bind to the ubiquitin component and then destroy the protein to which ubiquitin is attached. So it is not an enzyme in itself, but it serves as a universal signal for degradation of proteins.

I stumbled into it early in my PhD, when I was working in a laboratory at the John Curtin School with Philip Board to study glutathione transferase proteins. They are proteins in a cell that detoxify carcinogens we might take in from our diet or from insults like tobacco smoke. I actually obtained a gene for ubiquitin as a false positive in the first lot of screens I was doing. At the time, nobody had isolated a human ubiquitin gene, or the DNA that codes for ubiquitin in humans – there was only one paper reporting a sequence from yeast – so it was a very new area. A bit of biochemical study on ubiquitin had shown that it was involved in protein degradation, but it wasn't yet realised how fundamental this process was in controlling the activity of many proteins in the cell.

I was very lucky that the research environment I was in, with Phil Board and the Human Genetics Department, encouraged me to go off on this little tangent. Discovering the ubiquitin sequence was rather serendipitous in the first place, but it has kept me interested for the last 17 years.

What does the name 'ubiquitin' mean?

I guess the names that scientists give things must seem funny sometimes, but essentially this is called 'ubiquitin' because of its ubiquitous distribution and conservation. It's in every organism except the very simple bacteria. It is in the simple eukaryotes such as yeast, right through to ourselves, in every cell in our body. And it is the most strongly conserved protein known, the one that has changed the least during evolution. That is because it has this very fundamental role in destroying – very selectively – proteins in the cell.

Crucial roles for the ubiquitin pathway

We would all have heard that an important part of the way a cell works is by making lots of proteins. Is the destroying of the proteins as important?

It is absolutely critical. In a closed system such a cell, you can't keep synthesising new molecules without destroying the old ones. (Eventually the cell might build up and explode!) You need more synthesis than degradation because as a cell is dividing it needs to generate new material for the daughter cells it makes.

The ubiquitin pathway involves picking out, and specifically destroying, one protein from perhaps 1000 or 2000. Some of the proteins it destroys are molecules that are essential for regulating cell growth, division and development. It is critical that those proteins are produced at the right time and active, but it is just as critical that they are destroyed when the cell no longer requires them to be active. Just as the absence of a certain enzyme could be detrimental to cell growth, the overabundance or overactivity of a molecule could be detrimental to cell function, so it is critical to have a balance between synthesis and degradation. My view, perhaps biased, is that even these days the degradation aspect is a little bit overlooked. But I think it is being realised more and more how important the selective destruction of proteins is to the cell.

Might a knowledge of ubiquitin's role in this lead to any applications?

Oh definitely. In my lab my main interest is in the area of cancer research. Many of the proteins that ubiquitin is involved in destroying are ones that we might call oncogenes. They are proteins that would cause cancer if they were present at too high a level in the cell, so it is critical for the ubiquitin pathway to remove them from the cell, to stop them functioning.

One example from my research is that one of the enzymes we work on can snip ubiquitin back off a protein (one that we haven't identified yet). If we overproduce that enzyme in a cell, it can actually cause cancer; it will cause tumours in mice. So our model is that this enzyme, by snipping ubiquitin off the protein, is preventing degradation or destruction of the protein and keeping it at too high a level in the cell. And the protein goes on to promote unregulated cell growth, which is cancer.

So I'm interested in two aspects. One is the fundamental mechanisms of how ubiquitin is attached and removed from proteins, and how that regulates degradation of proteins. The other is research into cancer and other diseases where you have defects in cell growth or cell division because proteins are not destroyed before they promote too much cell growth.

Focus questions

• What is the role of ubiquitin in a cell?

• Do you think protein degradation is a critical part of the way a cell works?