Most of today's anticancer drugs target the DNA or proteins in tumor cells, but a new discovery by University of California, Berkeley, scientists unveils a whole new set of potential targets: the RNA intermediaries between DNA and proteins.
This RNA, called messenger RNA, is a blueprint for making proteins. Messenger RNA is created in the nucleus and shuttled out into the cell cytoplasm to hook up with protein-making machinery, the ribosome. Most scientists have assumed that these mRNA molecules are, aside from their unique sequences, generic, with few distinguishing characteristics that could serve as an Achilles heel for targeted drugs.
Jamie Cate, UC Berkeley professor of molecular and cell biology, and postdoctoral fellows Amy Lee and Philip Kranzusch have found, however, that a small subset of these mRNAs - most of them coding for proteins linked in some way to cancer - carry unique tags. These short RNA tags bind to a protein, eIF3 (eukaryotic initiation factor 3), that regulates translation at the ribosome, making the binding site a promising target.
"We've discovered a new way that human cells control cancer gene expression, at the step where the genes are translated into proteins. This research puts on the radar that you could potentially target mRNA where these tags bind with eIF3," Cate said. "These are brand new targets for trying to come up with small molecules that might disrupt or stabilize these interactions in such a way that we could control how cells grow."
These tagged mRNAs - fewer than 500 out of more than 10,000 mRNAs in a cell - seem to be special in that they carry information about specific proteins whose levels in the cell must be delicately balanced so as not to tip processes like cell growth into overdrive, potentially leading to cancer.
Surprisingly, while some of the tags turn on the translation of mRNA into protein, others turn it off.
"Our new results indicate that a number of key cancer-causing genes - genes that under normal circumstances keep cells under control - are held in check before the proteins are made," Cate said. "This new control step, which no one knew about before, could be a great target for new anticancer drugs.
"On the other hand," he said, "the tags that turn on translation activate genes that cause cancer when too much of the protein is made. These could also be targeted by new anticancer drugs that block the activation step."
The new results will be reported April 6 in an advance online publication of the journal Nature. Cate directs the Center for RNA Systems Biology, a National Institutes of Health-funded group developing new tools to study RNA, a group of molecules increasingly recognized as key regulators of the cell.