Now that I’m formally studying cancer biology, there was always bound to be exposure to some rather fascinating things which I’d then go on to blog about, duly. Today, I will be looking at Tumour suppressors and how several things can take place with respect to how they are knocked out and how this can have varied implications for tumourigenesis.
When tumour suppressors were discovered, it was found that there were genes that were capable of causing cells to hyperproliferate if knocked out. This meant that there were genes in cells whose normal function was to prevent cells from growing too much or too rapidly. For tumour suppression to fail, it appeared that both copies of a gene had to be knocked out, which is why fusing normal cells with cancer cells almost inevitably prevented the properties of cancer cells from manifesting.
The first tumour suppressor that was identified was the protein pRb. This was identified by looking at people who got the childhood tumour retinoblastoma and subsequently finding out that certain families which showed an inherited predisposition to retinoblastoma had inherited a dysfunctional copy of the gene.
It was later found that if there was a viral infection such as an adenovirus, it would prevent Rb from acting by blocking its binding to a family of transcription factors called E2F. This evidence led to the identification of the complete loss of Rb function as one of the mechanisms for tumorigenesis, especially in retinoblastoma. Knudson, on the basis of this, proposed a two hit hypothesis; i.e, there had to be two events that resulted in the knocking down of both of the copies of Rb before tumour suppression was lost.
The ways by which Rb function is lost is beyond the scope of the current post in any detail, but basically, unless phosphorylated by cyclin dependent kinases it binds to E2F, preventing it from activating the genes that are expressed to progress to the next phase of the cell cycle. If it is phosphorylated due to structural changes that prevent dephosphorylation, for instance, it loses the ability to bind to E2F in any case and therefore the cell cycle checkpoint it is active at fails.
An early review of pRb function may be found here
Knudson’s original paper on the two-hit hypothesis can be found here.
Think the two hit hypothesis sorted questions on tumour suppressors out? Think again, later research showed that some tumour suppressors, such as the ever-so-important p53 and p17 for instance, acted in a gene-dosage dependent manner. A brilliant illustration of this was provided when people produced mutant mice that had one copy of p17 knocked out, and both copies knocked out. They observed that those with one copy knocked out demonstrated hyperproliferation that was intermediate between that of normal mice and that of those which had both copies knocked out. This was called haploinsufficiency, i.e, if you knocked out just one copy of a tumour suppressor, it could still have a significant phenotypic effect. If reading scientific literature is your thing, you can read more about the genetics of tumour suppressors and tumour suppression here.
So, could we then classify tumour suppressors into those that required two hits or those that worked by haploinsufficiency, with no overlap? Surely it made sense that losing one copy was not as bad as losing both copies?
As it turns out, not quite.
Emerging evidence has led to the formulation of a continuum model, which seeks to indicate that the type of event needed to knock-out tumour suppression can be dependent on other genetic circumstantial factors too. In the apposite paper, Knudson et al refer to PTEN, where haploinsufficiency is more tumorigenic compared to complete loss if p53 function is good because deletion of both copies will trigger a p53 mediated failsafe reaction that kills the cell. However, if p53 is knocked out, losing both copies of PTEN is a good idea for cancer cells.
It would appear, as with most other things in oncology, context is key. That is all from me this time round.