Ribonucleic acid, or RNA, has long been thought to be
important only to translate a gene's DNA into the proteins
that are cells' workhorses. But new evidence shows that
tiny bits of RNA not used to make proteins actually play
central roles in normal biology and in the development of
"Scientists have known for a few years that production
of these tiny RNAs, known as microRNAs, is only supposed to
happen at certain times and in certain tissues, but no one
had been able to identify what controlled the timing," says
Joshua Mendell, assistant professor in the
McKusick-Nathans Institute of Genetic
Medicine. "We've identified the first such controller,
a well-studied protein called Myc. Our discovery fits in
quite well with the two other labs' studies on the
involvement of microRNAs in cancer."
The work from investigators at Johns Hopkins is one of
three papers on microRNAs in the June 9 issue of
Identified only a few years ago, microRNAs are known
to control the extent to which other genes can be used to
make proteins, by binding to and interfering with genes'
protein-building instructions. The microRNAs play roles in
cell division, cell specialization and cell death in worms
and flies and are off-kilter in human cancers, but the Myc
protein is the first factor identified that controls the
production of microRNAs.
Myc (pronounced "mick") is already known to regulate
about 10 percent to 15 percent of the genes in the human
genome, controlling the extent to which they are used to
make proteins. Myc also is faulty and overactive in many
human cancer cells, although exactly how it contributes to
cancer is unclear.
Given Myc's regulatory role and its involvement in
cancer, the Johns Hopkins researchers tested human cells to
see whether changes in the amount of Myc affected levels of
any of the more than 200 known microRNAs. Through these
experiments and others, they discovered that Myc directly
controls the gene for a set of six microRNAs in a region of
chromosome 13 that is already tied to development of human
MicroRNAs are made by the same cellular machinery that
makes other forms of RNA, like the messenger RNA used to
build proteins. However, microRNAs are immediately
processed by cellular machinery that deals with what is
known as RNA interference, a biological phenomenon that
specifically prevents RNA from being used to make
Accompanying the Johns Hopkins paper are two reports
looking specifically at microRNAs in cancer — one in
humans, one in mice. One report shows that human tumors'
microRNA "fingerprints" — patterns showing which of
the more than 200 known microRNAs are more or less abundant
than normal — identify the tumors' tissue of origin
much better than other tests. The other paper shows that
overexpression of chromosome 13's microRNAs dramatically
increases the risk of cancer in mice predisposed to cancer
because of a faulty Myc gene.
"We've found that there's complex cross talk between
Myc, the microRNAs and the genes that both control,"
Mendell says. "This complex system, if disturbed, has the
potential to very potently drive cell growth and cancerous
Among the genes Myc controls is one called E2F1. And
one of the genes controlled by E2F1 happens to be the gene
"This establishes a feedback loop," says Kathryn
O'Donnell, who conducted much of the work as a graduate
student in the Human Genetics Program. "Because both Myc
and E2F1 increase the expression of genes that increase
cell growth, the pair could be quite dangerous if they
simply fed off each other."
But the researchers also discovered that two of the
six microRNAs controlled by Myc actually reduce cells'
ability to use E2F1's protein-building instructions.
Essentially, these microRNAs act as a "brake" to slow
E2F1's growth-promoting effects.
"So the Myc protein 'turns up' the genes for E2F1 and
the microRNAs, but the microRNAs reduce the amount of E2F1
protein that can be made, fine-tuning Myc's effects,
perhaps," Mendell says. "We chose to look for interactions
with E2F1 specifically, but there are bound to be many,
many more genes that these microRNAs regulate."
"Whether too much or too little of these or other
microRNAs is a good thing or a bad thing — whether it
would contribute to or help prevent cancer — depends
on their targets in the cell," adds Myc specialist Chi
Dang, the Johns Hopkins Family Professor in Oncology
Research and a professor of medicine in the
McKusick-Nathans Institute and the Kimmel Cancer Center.
"Slowing E2F1 production would seem to be a good thing
because doing so would slow cell growth, but that might not
be the case for other genes controlled by these
Encoded for by genes' DNA, just like other RNA,
microRNAs start out more than 1,000 building blocks long.
Because they are able to fold back on themselves, they form
double-stranded RNA rather than the single strand
characteristic of messenger RNA. As a result, the cell
breaks the RNA into pieces. All sections except the
microRNAs, just 21 to 23 building blocks long, are
The microRNAs can bind to single-strand messenger RNAs
of the right sequence, a process that at the very least
interferes with their ability to be read to make proteins
and sometimes leads to the RNAs' destruction.
"Now we're figuring out the functions of these
Myc-controlled microRNAs, other genes they regulate and how
else they might be involved in Myc-mediated initiation of
cancer," says O'Donnell, who conducted her graduate work in
The research was funded by the National Institutes of
Health, the March of Dimes and a Sidney Kimmel Pilot
Project Grant. Authors on the paper are O'Donnell, Dang,
Mendell, Erik Wentzel and Karen Zeller.