Date Published: May 20, 2008
Publisher: Public Library of Science
Author(s): Thomas A Hughes, Pamela F Jones
Abstract: Thomas Hughes and Pamela Jones discuss the implications of a new study on the 5′ non-coding region of vascular endothelial growth factor mRNA and its influence on gene expression.
Partial Text: In the last decade or so, we have become familiar with the discovery of new classes of nuclear-encoded regulators (see Glossary) as fundamental controllers of gene expression. Each new discovery has again highlighted the incomplete nature of our understanding of the genome and its regulation. First, small interfering RNAs (siRNAs) demonstrated that RNA molecules are not merely components of the cellular machinery (such as tRNAs and rRNAs) or gene-expression intermediates (mRNAs), but can function as potent trans-acting regulators of specific genes. MicroRNAs (miRNAs) continued this theme and now attract much attention among basic scientists and clinicians alike, both as potential regulators of most human genes and as potential diagnostic tools. In this issue of PLoS Medicine, a research article by Shigetada Teshima-Kondo and colleagues supports the suggestion that another class of regulatory RNAs exists . Furthermore, this class could be the largest to date, since potential members are contained within every mRNA.
The authors show that the 5′ untranslated region (UTR) of the vascular endothelial growth factor (VEGF) mRNA influences expression of other genes, and thereby cell function, independently of the VEGF reading frame. Many UTRs have long been known to function as cis-acting elements on the expression of their own mRNAs [2,3]—but trans-acting regulatory functions are an exciting possibility, which, if commonplace, would be every bit as influential as siRNAs or miRNAs.
While the idea that mRNAs might have functions that are independent of their translation may be surprising, there are published precedents for related trans-acting functions of UTRs. Such examples remain few and far between (Teshima-Kondo et al. cite four, and we have found a further two [9,10]) and have not had a significant impact on the general consciousness of researchers. This new work represents an important advance, in that the function takes place in the context of a key player in carcinogenesis that is already used as a cancer therapy target, and therefore the study highlights this class of regulation. What this new study shares with its precedents, however, is the lack of a defined mechanism of action. As such it is difficult to determine the generality of trans-acting functions of UTRs, and it is too early to start considering mRNAs as another class of fundamental gene regulators.
It is possible to postulate a variety of mechanisms by which UTRs might exert trans-acting influences. First, the RNA-activated protein kinase (PKR) may be activated by binding to double-stranded regions of UTRs. Activated PKR is well known to cause changes in the translational efficiency of certain mRNAs as part of the cellular response to viral infection, but more recently has been implicated in other pathways, including cancer-related mitogen-activated protein kinase signalling . PKR has been shown to bind to one published trans-acting UTR , and Teshima-Kondo et al. report preliminary data (although these are not shown) indicating that PKR may bind to the VEGF mRNA.
This study has a clear implication for VEGF-targeted therapies, in that strategies to target the mRNA may be required to inhibit the full oncogenic influence of the gene. More generally, the study highlights a little-studied gene regulatory pathway that may yet prove to be far more commonplace than currently appreciated.