Saturday, April 26, 2008

Pluripotency and Lin28

As we discussed here, pluripotent stem cells have been obtained by "reporogramming" various kinds of adult cells. In one case, a set of 4 transcription factors – Oct3/4, Sox2, c-Myc, and Klf4 – were used for the reprogramming. Another research team used a slightly different set – Oct3/4, Sox2, Nanog, and Lin28.

Two of the transcription factors are the same in these two sets. Of those that are different, c-Myc and Nanog are very familiar to molecular biologists for a variety of reasons. (We discussed some of what's known about c-Myc here, and Klf4 is discussed here.)

So what, if anything, is special about Lin28? Quite a lot, it turns out. Apparently Lin28 not only promotes pluripotency, but it also interacts with a very well-known type of microRNA called let-7. As we saw here, let-7 does several things that help suppress cancer. For one thing, let-7 regulates the oncogene Ras, apparently by binding to the mRNA encoding Ras, thereby inhibiting protein expression. (See here.) For another thing, and more to the point, let-7 tends to negate some of the "stemness" of stem cells, and pushes them onto a path for differentiation into more specialized cell types. (See here.) This helps inhibit cancer by reducing the ability of suspected cancer stem cells to proliferate. Let-7 has also been mentioned as an inhibitor of oncogenicity of c-Myc.

Lin28, on the other hand, seems to regulate let-7, and therefore it helps preserve "stemness", but at the same time it may raise the risk for development of cancer. A paper in the April 4 issue of Science describes the research that indicates such activity:

Selective Blockade of MicroRNA Processing by Lin28
Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.

Some people are suggesting that perhaps at least some "cancer stem cells" are actually more ordinary cancer cells that have been reprogrammed (in part by Lin28) to be capable of more stemcell-like behavior. What's really going on here still seems a bit speculative at this point.

This blog post of 3/25/08 goes into a lot of detail on mircoRNA, let-7, Lin28, and the whole ball of wax: bring 'em all together: cancer, stem cells, miRNAs.

Further reading:

Deconstructing Pluripotency – overview article in April 4, 2008 Science that discusses two stem cell papers, including the one cited above

Let7 miRNAs, Lin-28, Cancer and Stem Cells – 3/24/08 blog post that discusses this research

Lin-28 is Master of Let-7 miRNA Processing – 3/25/08 tongue-in-cheek blog post that discusses the previous blog post and the subject more generally

Tid Bits – 3/28/08 blog post on related topics

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