Tuesday, January 18, 2011

p21 and regeneration.

A few days ago an article did the rounds on the regeneration of limbs in mammals being possible with the deleteion of a single gene. It's been known for some time that the humans have all the genes neccesary for limb regeneration, a set of genes very similar to lizards that can regenerate. The major difference being that when we lose a limb, the genes don't turn on.

A group from the Wistar Institute have published details of p21 knockout mice that appear to be able to regenerate limbs. p21 is a gene involved in the regulation of the cell cycle. There are various cyclin dependent kinases (CDK) floating around in a cell that help move a cell from a state of growth to a state of homeostasis and vice cersa. p21 binds to some of these CDK's and prevents the cell from moving into a growth phase. So by knocking out this gene in mice, the researchers appear to have been able to allow growth to move forward and the correct form of growth to progress to allow for limb regeneration.

The trouble with this is the p21 is part of the p53-tumour suppressor pathway. Basically, the p53 gene is turned on in response to DNA damage, which turns on p21 which in turn blocks the cell from replicating. Ideally, you do not want a cell to grow and replicate if it is damaged, so this a good thing. In fact, a damaged p53 gene is quite common in a variety of cancers, when the mechanism to stop damaged cells replicating is damaged, things go a little haywire and the damaged cells, can become cancerous.

p53 is not the only thing that turns p21 on though. And the fact that knocking p21 out allows limb regeneration is a pretty good indication of that. It does pose the question of how and what is activated. For limb regeneration to occur, cells at the end of the damaged limb must dedifferentiate - become more like stem cells that can turn into any other type of cells - and then grow and re-differentiate - turn back into the various types of limb cells. This makes it look like p21 is a generic tool that is used to block cell growth that p53 uses when it finds damaged DNA. Over the past year or two, several methods have been demonstrated that turn cells back into pluripotent stem cells. None of them have, that I can recall involved p21, which leads me to think that there is some other gene turned on when a limb is damaged that turns p21 to allow regeneration. Which is interesting, but still dangerous. If we figure out methods of turning p21 off, we are potentially sodding around with one of the core mechanisms that prevent cancer, interesting, but dangerous.


  1. If I am not mistaken, haven't scientists already shown that turning off p21 does not mean a growth in cells turning cancerous is going to happen. Haven't studies shown that actually what is happening is not cancer growth, but the damaged cell already have a mechanism that causes "cell Death".

  2. If I recall correctly (and it's been a while since I looked at cancer biology, I'm looking at plant immune responses these days) turning p21 off doesn't mean that cancer will occur, no. It does increase the risk though, it's one of the mechanisms the cell uses to keep growth in check - not the only one.
    Programmed cell death - generally called apoptosis (it's greek I think) can be kicked off by a number of different factors, damage to the cell being one of them.

    One of the things that really took my breath away when I got into biology was the realisation that these pathways (i.e p53->p21->something else) are just threads through a network. i.e. there are multiple different things that affect each step in the pathway. and the balancing of those networks is what keeps the cell alive.