RNA Journal Club 7/1/10
A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
Laura Poliseno, Leonardo Salmena, Jiangwen Zhang, Brett Carver, William J. Haveman & Pier Paolo Pandolfi
Nature 465: 1033–1038, 24 June 2010.
doi:10.1038/nature09144
No formal write-up for this week, rather just some points to consider, raised during our journal club discussion:
The authors’ probing of expression levels in prostate cancer cells showed that PTENP1 was expressed at much lower levels, perhaps up to 100-fold less, than PTEN. If this is true, how can CMV driven overexpression of PTENP1 RNA come close to recapitulating the relative levels and biological interactions of these two transcripts in the cell? The abundance of each transcript will strongly influence their abilities to act as miRNA sponges for one another. This concern wasn’t really alleviated even when they looked at expression in normal human and prostate tissue samples.
Since their central argument was that PTENP1 acts as a sponge for miRNAs that can also bind PTEN, since many miRNA binding sites are present in both transcripts, they were remiss in not showing the effect of expressing the PTENP1 3’UTR with mutated miRNA binding sites. This is a crucial control. While they showed that there is a difference in expression when the sites are mutated, using luciferase reporter constructs, the difference was small for the number of sites they predict are targeted by various miRNAs.
They also observed PTENP1 overexpression reduced colony formation significantly more than repressing PTEN protein alone, indicating expression of PTENP1 is important for reasons other than regulating how miRNAs bind PTEN (perhaps also not surprising given the near perfect maintenance of a large block of nucleotide sequence between the gene and pseudogene, not just the miRNA binding sites). Together, the data don’t provide adequate support to the authors’ claim that PTENP1 is an endogenous miRNA sponge for PTEN.
Update 7/8/10: A quick search for this paper on the web revealed it is quite popular with the ID folk–they’re eating it up good! And then I found the press release from Beth Israel Deaconess Medical Center, where Dr. Pandolfi says:
… not only have we discovered a new language for mRNA, but we have also translated the previously unknown language of up to 17,000 pseudogenes and at least 10,000 long non-coding (lnc) RNAs. Consequently, we now know the function of an estimated 30,000 new entities, offering a novel dimension by which cellular and tumor biology can be regulated, and effectively doubling the size of the functional genome.
Oh, well if you put it that way… now I see why it was in Nature.
Citation for researchblogging.org:
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, & Pandolfi PP (2010). A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature, 465 (7301), 1033-8 PMID: 20577206
Update 9/8/15:
The Reproducibility Project: Cancer Biology is attempting to reproduce some results central to this study. Godspeed to you!
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