Wednesday, January 02, 2008

p53 & microRNA

My extreme originality for a post specifically for the cancer research blog carnival resulted in me checking out the top 20 downloaded articles from one of the top cancer research journals, Cancer Cell. Number 15 at the time of posting was "p53 enters the microRNA world" (short free abstract). This one is near and dear to me.
p53, "the guardian of the genome" is a particularly intensely studied tumour suppressor protein because it has been found mutated in almost all cancer types. It is a transcription factor that regulates/coordinates important and diverse cell fate programs such as cell cycle, apoptosis (programmed cell death), DNA repair and senescence. What is new about p53 in this cell paper (review subscription required) is that another transcriptional target has been identified as the microRNA family miR-34.
MicroRNAs are small RNAs that repress translation of target mRNAs. Target mRNAs contain partially complementary sequence in their 3'untranslated regions (3'UTR). New functions, activities and mRNA targets of microRNAs are being discovered at a rapid pace as researchers try to catch up on this important mechanism of gene regulation that has been a large oversight until their relatively recent discovery.
An connection between microRNAs and p53 is that in addition to specific transcription activation of genes, p53 has also been found to inhibit expression of some genes, for instance those involved in cell cycle. Since this is the function of microRNAs perhaps this was a mechanism by which p53 can mediate some of its effects. Also it is becoming obvious that aberrant expression of microRNAs accompanies cancer phenotypes.
A barrage of papers in late 2007 showed that the miR-34 family are direct transcriptional targets of p53. So the question was if p53 has all these important cellular function how much of that can be attributed to the microRNAs transcribed by activated p53? As it turns out quite a bit. Expression of miR-34 microRNAs results in cell cycle arrest, inhibited colony formation, senescence, tumour cell senescence, and apoptosis in various studies. And based on inhibition of miR-34, it is possible to say that miR-34 may be sufficient and required for tumour suppression by p53. Also important miR-34 mRNA targets were identified as crucial genes involved in cell cycle and apoptosis.
Interestingly miR-34 loss is observed in neuroblasoma, its expression is low or undetectable in 11 of 15 pancreatic cancer cell lines, and its expression is decreased by more than 90% in 6 out of 14 lung cancers.
So in summary, perhaps the tumour suppressing function of p53 is mediated through small RNAs! Obviously p53 itself is required in the cell but these studies point to novel therapies involving restoration or ectopic expression of miR-34.


Bayman said...

So p53 protein-coding and miRNA encoding genes are doing the same thing. How does the whole system work? Are these findings demonstrating redundancy or co-operation?

Interestingly, these findings offer a possible mechanism for a direct coupling between transcriptional and post-transcriptional (translational) regulation. It would be interesting to know whether p53 transcriptional targets are also miR-34 targets.

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