RAS is regulated by miRNAs

I have already discussed one of the newest papers on miRNA-mediated control of oncogenes and cell pluripotency in the field a few days ago. Given the interest, also in the science blogosphere, for studies and news related to miRNAs, I thought I might write here about a few more papers focusing on how miRNAs are able to modulate the protein levels of several genes important for the regulation of major signal transduction pathways, as well as cell growth and differentiation.

Today I am going to be looking at the one that must be the first paper in the field to report the discovery that at least a family of miRNAs, the let-7 family - which you have encountered before on this blog - is able to regulate a major oncogene, RAS. For short review on what miRNAs are, you can check this out. Now, if you are ready...there's more, right below the fold.

This paper starts by looking at the role of the let-7 of miRNAs in vulva development in C. elegans, the nematode. As I have explained in a previous post, C.elegans come in two sexes: a few rare males, and the most common hermaphrodites. The hermaphrodites are able to produce eggs and self-fertilize them, therefore being able to generate progeny on their own. However, from time to time hermaphrodites will mate with males, and the male sperm will fertilize the hermaphrodite's eggs and generate both male and hermaphrodite progeny. The two sexes have distinct primary sexual characteristics identifiable in their genital apparatus, and the hermaphrodite has a vulva, while the male has a fan-like structure at the posterior end.

Vulval development is an excellent model for studying development at the cellular level (how cell lineages are defined), but also to dissect a major signal transduction pathway, the RAS/MAPK pathway, which is involved not only in development, but also in tumorigenesis.

In the course of the analysis of the effect of let-7 miRNAs on vulval development, Johnson et al. realized that these miRNAs can bind to a section of the 3' untranslated region of the C. elegans RNA equivalent of RAS, let-60 (lethal-60). In fact, this gene has let-7 complementary sites (LCSs) that allow the miRNAs to bind and inhibit its translation. Moreover, let-7-mutant animals will burst through the vulva, while they will not burst if let-60 protein expression is also inhibited by RNAi. This is shown in the following figure.



This finding prompted the authors to look for LCSs in the sequence of the human RAS genes (there are multiple versions of RAS). The human RAS genes also show the presence of LCSs, and are regulated by the human version of let-7 family miRNAs. Injecting let-7 in RAS-expressing cells reduces the levels of expressed RAS protein, and conversely inhibiting let-7 in let-7-expressing cells causes a rise in the levels of intracellular RAS (see figure below).



RAS overexpression or unregulated activity is known to be oncogenic, and many tumors show abnormal regulation of RAS. The authors then looked at human tissue samples derived from patients suffering from breast, colon and lung cancer, and compared levels of let-7 expression, and RAS protein in this samples, to those in adjacent normal tissue from the same patients. The experiments showed that let-7 expression was severely altered in lung cancer samples, and that when let-7 was not expressed at normal levels, this resulted in an increased load of RAS.



This study was of great importance at it showed a direct relationship between let-7 and RAS levels, as well as suggesting that miRNA regulation can be important in tumor biology, and possibly oncogenesis.

Citation

JOHNSON, S., GROSSHANS, H., SHINGARA, J., BYROM, M., JARVIS, R., CHENG, A., LABOURIER, E., REINERT, K., BROWN, D., SLACK, F. (2005). Is Regulated by the MicroRNA Family. Cell, 120(5), 635-647. DOI: 10.1016/j.cell.2005.01.014

Blogroll Additions

Dispatches from the Culture Wars - how did I miss adding this link to my blogroll for so long? Well, here it is.

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