In innumerable spy movies, the hero or a villain imprints a key in clay in order to later make an exact copy. In the body, the clay is messenger RNA, or mRNA, which imprints a gene and transfers the plans to a ribosome, where the mRNA's code is manufactured into a protein – the shady shop where the clay imprint becomes a key.
It's the body's job to recognize and destroy cancerous clay molds in transit – any mRNA that codes for an oncogenic protein. Only, the body frequently fails and mRNA that should be killed is instead allowed to be turned into its cancer-causing protein product.
The National Cancer Institute identified the method by which cancerous mRNA evades the body's safeguards as one of the 24 most provocative questions in cancer science. And the NCI Provocative Questions Project has entrusted the search for an answer to David Bentley, PhD, investigator at the University of Colorado Cancer Center and professor in the Department of Molecular Biology at the CU School of Medicine.
"mRNAs have a long tail of residues that won't necessarily be expressed in the protein it codes for," Bentley says. "And it was realized that many of these tails, called poly(A) tails, are mislocalized in cancer cells."
So, what difference does it make if an mRNAs extra, unexpressed tail is missing or in the wrong place? Well, "When you cut off these untranslated sequences, you can end up with runaway mRNA – when it loses those important pieces at the end, it can escape from regulatory mechanisms that can keep it under control."
The body looks for an mRNA's poly(A) tail as a signal to make a thorough examination. Without this tail, or with an unrecognizable tail, cancerous mRNAs evade scrutiny.
In addition, Bentley describes the length of an mRNA's poly(A) tail effecting its stability. A stable mRNA stays still near the ribosome and allows itself to be easily read and copied; an instable mRNA turns over rapidly and is less likely to be made into a protein. And a mRNA's poly(A) tail presents docking bays at which regulators of this stability can attach – proteins and microRNAs that land at poly(A) tails can hold an mRNA stable for expression or make it instable and unreadable.
These tails are not easy to see. In fact, they're virtually invisible to traditional cancer scientists who have been most concerned with exploring patients' genomes for the mutated genes that cause cancer – either oncogenes that are upregulated or tumor suppressor genes that are downregulated. These mutations result in changes in the sequence of proteins, the products of which are dangerous new stuff.
"But this new mechanism of corrupted poly(A) tails opens up a new way in which a gene can be activated or inactivated without a mutation. Nobody has ever looked for the positions of these tails in the past – and it wouldn't' show up by genetic sequencing," Bentley says.
In fact, the poly(A) tails are generally invisible to the traditional techniques of cancer scientists. That's why it may take Bentley's view from outside this cancer science box to discover an answer.
"I'm not actually a cancer scientist," admits Bentley. "In fact, I've never had a grant from the NCI before. It's only through the generosity of researchers at the CU Cancer Center including Ross Camidge in lung cancer and Anthony Elias in breast cancer that I've been able to frame my lab's rather unique expertise in the maturation of mRNA in terms of its potential clinical impact on cancer."
"The collegiality on this campus made this project possible," Bentley says.
In a year we'll know if this nexus of diverse scientific expertise along with more than a quarter million dollars from the NCI will result in an answer to one of cancer science's most provocative questions: how mRNA tails promote cancer. The answer could provide an entirely new way to intervene in the chain of events that leads from bad genes to cancerous proteins.
About the National Cancer Institute's Provocative Questions Project
The Provocative Questions project emerged from discussion among a number of veteran cancer researchers that noticed there were many questions — some important but not very obvious, some that had been asked but abandoned in the past because we didn't have ways to study or address them, some sparked by new discoveries or novel technologies — that could stimulate the NCI's research communities to use laboratory, clinical, and population sciences in especially effective and imaginative ways. Over the course of 18 months, NCI solicited questions from scientists in various fields and at different stages in their careers, ultimately settling on 24 questions that, if answered, could lead to significant research advances. For instance, scientists have known for a long time that obesity contributes to cancer risk, but we don't know why this is the case, so one of the questions challenged researchers to address this very phenomenon. In a departure from its traditional grant-making process, NCI released a special solicitation just for research related to these 24 questions and empaneled a custom set of peer review groups to score the more than 700 applications NCI received. More than 50 grants, attempting to answer 20 of the 24 proposed questions, are being funded this year from that set of applications. These grants are not intended to represent the NCI's full range of priorities in cancer research, but rather represent a new and different way to identify and address research needs in cancer by challenging researchers to delve into key areas that require more in depth study.
More than $22 million will be distributed amongst 57 grant recipients nationwide. Each research team has been tasked with the goal of attempting to answer one of 20 Provocative Questions. Though each grant tackles a very discrete question, the combined impact of the grants in the program is substantial. By identifying a specific set of questions, this project has focused resources to address critical questions that, if answered, have the potential to substantially change the way that scientists approach cancer research. These awards are intended to initiate new ways of approaching unanswered questions of great concern to scientists, ultimately jump starting additional investments when further scientific opportunities surface.
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