MicroRNA helps prevent tumors
CAMBRIDGE, Mass. (February 22, 2007) — A microRNA
directly regulates a gene implicated in human cancers,
researchers from Whitehead Institute and Massachusetts
Institute of Technology report in the February 22nd
online issue of Science.
MicroRNAs are tiny snippets of RNA that can repress
activity of a gene by targeting the gene's messenger
RNA (which copies DNA information and starts the process
of protein production).
The first microRNA was discovered in 1993, in worms.
It took seven years for the second one to be found,
also in worms. But then the floodgates burst. Many microRNAs
now have been found in diverse plants and animals, including
hundreds in humans. Moreover, microRNAs found in mammals
regulate over a third of the human genome, as shown
in a 2005 study by the lab of Whitehead Member and Howard
Hughes Medical Institute Investigator David
Bartel and colleagues.
“Because hundreds of human genes appear
to be regulated by the let-7 microRNA, we were
afraid we wouldn't see any difference when we
changed only one of these target genes,”
says Whitehead Member David Bartel. “Seeing
the difference encourages us to explore the biological
importance of other examples of microRNA regulation.” |
But given the wealth of microRNAs, and the ability of
individual microRNAs to target hundreds of genes, researchers
have struggled to show the biological impact of a particular
microRNA on a particular target in mammals (although
such connections have been shown in plants, worms and
flies). Several groups have demonstrated that over-expression
or under-expression of a microRNA can play a role in
certain cancers, but have not clarified the genes responsible.
Looking to find a promising target for an individual
microRNA, Christine Mayr, a postdoctoral researcher
in the Bartel lab, picked Hmga2, a gene that is defective
in a wide range of tumors.
In these tumors, the protein-producing part of the Hmga2
gene is cut short and replaced with DNA from another
chromosome. Biologists have mostly focused on the shortened
protein as the possible reason that the cells with this
DNA swap became tumors. But this DNA swap removes not
only the gene's protein-producing regions but also those
areas that don't code for protein. And these non-protein-producing
regions contain the elements that microRNAs recognize.
It turns out that in the non-protein-producing region,
Hmga2 has seven sites that are complementary to the
"let-7" microRNA, a microRNA expressed in
the later stages of animal development. Mayr wondered
whether loss of these let-7 binding sites, and therefore
loss of regulation by let-7 of Hmga2, might cause over-expression
of Hmga2 that in turn would result in tumor formation.
To find out, Mayr created a series of Hmga2 genes in
which various numbers of let-7 sites were destroyed.
She found clear evidence that when exposed to let-7,
the fewer sites that were intact, the more protein was
produced.
Next, she tested whether disrupting let-7's ability
to repress Hmga2 would lead toward tumor creation. In
a standard in vitro test of cancer-causing genes, colonies
of mouse cells that expressed normal or shortened Hmga2
did not grow significantly, while cells in which Hmga2
contained disrupted let-7 sites did. In fact, the more
that let-7 sites were damaged, the greater the number
of colonies.
Mayr also worked with MIT assistant professor Michael
Hemann to inject these cells in mice with a compromised
immune system. The scientists found that the mice with
cells that expressed the version of Hmga2 with the disrupted
let-7 sites developed tumors.
Overall, the results highlight a new mechanism for cancer
formation. Hmga2, and perhaps certain other genes that
are normally regulated by microRNAs, can help give rise
to tumors if a mutation in the gene disrupts the microRNA's
ability to regulate it. In addition, the results show
that the interaction of one microRNA with one of its
target genes can produce a certain trait in mammals.
This is important because scientists are only beginning
to learn the functions of microRNAs in animals.
"Because hundreds of human genes appear to be regulated
by the let-7 microRNA, we were afraid we wouldn't see
any difference when we changed only one of these target
genes," says David Bartel, who is also an MIT biology
professor. "Seeing the difference encourages us
to explore the biological importance of other examples
of microRNA regulation."
This research was funded by the National Institutes
of Health.
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