Research team corrects mistake on protein linked with cancer
A previously held belief about the behaviour of a human protein that is linked to the formation of cancer is being challenged. The study in question, published in the Journal of Biological Chemistry, will lead to new research into ways to prevent the protein from 'turning on' genes that are involved in the process of abnormal cell production. The research was partially supported by the MAP Kinase project, which received funding under the 'Quality of life and management of living resources' budget line of the EU's Fifth Framework Programme (FP5).
"The body is made up of cells that communicate with each other and with external cues via receptors at their surfaces," said lead author of the study, Professor Diane Lidke from the University of New Mexico in the US. "To generate cellular responses, signalling pathways are activated that initiate movement of proteins to specific locations inside the cells, notably the nucleus where DNA is situated."
One of these pathways is the extracellular signal-regulated kinase (ERK), which is altered in about 30% of human cancer cases. Researchers have suspected for a long time that alterations in this pathway could be responsible for the mutation that causes cancer.
The role of ERKs is to act as messenger molecules by relating signals received from outside the cell to the nucleus. To do this, the ERK has to move from its home in the intracellular fluid to the nucleus of the cell where it turns on several genes and turns off others. This process eventually tells the cell to divide or differentiate.
For the past 10 years scientists have believed that two molecules of ERK had to make a pair with each other after being activated in order to enter the nucleus, but the new study shows that protein pairing is in fact unnecessary for the ERK to enter the nucleus.
"Instead, the process was found to be dependent solely on the rate at which stimuli activate the ERK," explained Dr Philippe Lenormand from the University of Nice in France, a member of the research team.
The roots of this research go back to 1998 when a team of scientists created a mutant form of ERK while they were studying it. The team noticed the mutant form entering the nucleus of a cell in an abnormal way. But in the latest research and in other independent tests, results showed the mutant entering the nucleus in the same way as normal ERKs.
"Our work has clarified this field by reconciling existing data that seemed conflicting at first glance," said Dr Lenormand. "The entry in the nucleus of the mutant and the exchange in and out of the nucleus were slower than normal ERK, which could explain why the 1998 observations resulted in the conclusion that the mutant never made it inside. It was all about timing."
Professor Lidke noted that the fact that the mutant is activated with delay correlates with the delayed entry into the nucleus. "As a consequence, it is the first time that a delay in activation is reported to trigger a delay in nuclear entry of ERK, indicating that ERK entry into the nucleus is a direct consequence of activation," she said.
The new research will hopefully lead to a better understanding of the process of how ERK nuclear migration is regulated and consequently to the development of new therapies to control how it affects genes involved in abnormal cell proliferation. This is also important with regard to clinical trials of chemicals that block the activation of ERK.
"The improved understanding of ERK signalling by this study will open new lines of research," commented Dr Lenormand. "This is important, because this signalling pathway is deregulated in many cancers and essential for cognition, memory formation and cell differentiation."
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