The p53 barcode – a brief introduction.

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p53 may be one of the most famous proteins in all of oncology, with in excess of a million hits on Google scholar for a strict keyword search. This, perhaps, is due to the myriad of interactions it has with signalling pathways in cells. It can modulate a variety of responses, ranging from growth arrest in the case of DNA damage, to cellular senescence, to apoptosis. This happens in response to cellular stress signals.

p53 responses and core network.

Now, the presence of a multitude of responses immediately begins to raise questions; what might trigger one response as opposed to another? Could the level of free p53 be one determinant? Apparently, this is one of the mechanisms that does play a role, however, it would appear that it is far from the sole determinant. The explanation offered for how this might take place hinges on promoter affinity, if p53 levels are low, it might roughly tend to preferentially bind to high-affinity promoters, which might be associated with cell cycle arrest, and if levels are high an apoptotic response may be preferred. See here for a reference.

The same paper also does note that the aforementioned roles aren’t strictly followed. What else, then, might determine how p53 functions? A combination of post-translational modifications and the trigger that sets off the p53 response to stress signals are good candidates, and it is these that will be the focus of this article.

Now, writing a thesis on p53 post-translational modification is not what I’m going to do; I’m just going to mention that there are a multitude of these modifications and these can have significantly different effects on what p53 does, cue an illustration…

p53 map of posttranslational modifications.

Image source – http://www.bnl.gov/biology/cellbio/human_p53.asp

Some of these post-translational modifications act by changing promoter selectivity/affinity. An illustration from the primary reference for this article follows.

p53 PTM - Modifiers, modifications, and target genes.

Then there are some proteins and protein interactions that tend to affect promoter-selectivity directly…

Factors that affect p53 promoter selectivity directly.

Some other modifications can affect p53 by controlling where in the cell it is localized. Yet other factors include proteins that serve as cofactors that can enhance the transcriptional activation that p53 executes on target genes, and yet some others, most notably Mdm2, can directly bind to p53 and ubiquitylate it, breaking it down. To put it simply, there is a lot of flexibility in p53 activity that enables it to tweak the response it elicits to different inducers.

So, how would one go about representing this? One solution is a p53 barcode. This is far from ideal because it doesn’t really map out the fine details of what is going on, but it does simplify the representation of the processes involved.

Here’s one more illustration.

p53 is activated by an array of cellular stresses and responds by activating various signalling pathways that are involved in diverse cellular mechanisms, from apoptosis to DNA repair. The protein level, localization, post-translational modifications and the cofactors of p53 are crucial to the function and regulation of p53. We propose that each individual aspect of p53 regulation represents a bar from a barcode that directs p53 activity. Different combinations of bars form different barcodes, and the barcode dictates which response p53 induces, be it apoptosis, cell-cycle arrest or senescence. Importantly, this allows p53 to be activated in a manner that is stress and cell-type dependent. The diagram shows a range of p53 regulations that control p53 activity and, ultimately, determine the cellular response. This response may be transcription dependent or independent. Each regulator is illustrated with its own bars. The number and width of the bars was assigned arbitrarily and has no relevance to the importance of each aspect in the regulation of p53 activity. From the main reference (see end of post)

The reason I think that this is particularly elegant is simple; the actual network is rather dizzying in its apparent complexity and this form of representation can really highlight what variations exist in terms of the activity of the protein. As an aside, at this juncture, I wish to introduce one or two papers that describe how p53, through miRNA, can suppress metastasis. http://jem.rupress.org/content/208/5/875.short & http://jcb.rupress.org/content/early/2011/10/19/jcb.201103097.short

Finally, if you fancy taking a peek at the various pathways that p53 is involved in, you might find this collection from the Nature-NCI Pathway Interaction Database useful.

Reference : Zmijewski et al A complex barcode underlies the heterogeneous response of p53 to stress. Nature Reviews Molecular Cell Biology 9, 702-712 (September 2008). The paper is behind a paywall, but using Google Scholar you may be able to find an institution that has a PDF copy online somewhere.

That is all from me this time round.

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One response to “The p53 barcode – a brief introduction.

  1. Pingback: A Bird’s Eye View of Cancer Research… | Exploreable

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