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Tumor Suppressor Gene Gets a Little Help from MicroRNAs

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Often called the guardian of the genome or the master tumor suppressor gene, p53 has long been known to keep tumors at bay. Now, recent research shows that three microRNAs help p53 out, especially in preventing lung cancer. Previous studies focused mainly on the coding genes that p53 regulates, but recently, researchers have begun to take an interest in non-coding genes’ roles in tumor development as well, says Guido Bommer, a postdoctoral fellow in Eric Fearon’s lab at the University of Michigan.

“The question was: is anything known about … non-coding genes being targeted by p53? We immediately set out to find out whether any of these short, non-coding microRNA could be targets for the trans-activating action of p53,” says Bommer, lead author of a paper in Current Biology reporting these results. “The whole family [of microRNA34] actually is activated by p53.”

Using reporter gene constructs, gene expression assays, and chromatin immunoprecipitation, Bommer and his colleagues found that p53 regulates three members of the microRNA34 family and that these microRNAs mediate p53 function. By overexpressing the microRNAs, they found that the cells would stop proliferating, just like with p53. Furthermore, when these microRNAs were knocked out, the cells were protected from apoptosis. Then, through western blot analysis, they saw that the microRNAs down-regulated the anti-apoptotic factor BCL2.

“To me, it was very surprising that a group of three very highly related genes is targeted by the same pathway,” says Bommer.

Lungs normally express high amounts of microRNA34b and c, so Bommer and his colleagues looked to see if the loss of either of these microRNAs was correlated with lung cancer. “That’s why we studied lung cancer and saw that in something like 40 percent of non-small cell lung cancer, we see a very strong down-regulation of these two microRNAs — suggesting or consistent with the idea that there is a selective advantage for losing the microRNAs’ expression during the development of these types of lung cancer,” Bommer says. When the microRNAs were reintroduced into non-small cell lung cancers, their growth was inhibited.

But how the two microRNAs get turned off in this type of lung cancer is not yet known. The scientists have so far ruled out promoter methylation and gene loss. “The transcription of the genes seems to be shut off by a mechanism that we do not know yet,” Bommer says. But they are working on it.

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