"Activating mutations in the NF-кB pathway does not generally represent the initial oncogenic event," Dr. Pagano said. "But they are necessary for the survival and spread of the cancer."
Dr. Pagano explained the steps involved with pathway's activation and deactivation in more scientific detail: The process begins in the pathway's off state, with the accumulation of p100. To clear the pathway and naturally turn it back on, a sequence of events has to happen. First, a kinase, which the team identified as GSK3, phosphorylates p100. The phosphorylation draws the attention of Fbxw7α, a subunit of a ubiquitin ligase, which binds to the portion of p100 that has been phosphorylated by GSK3. The addition of Fbxw7α to the p100 protein then causes ubiquitin to seek out p100. Ubiquitin attaches to the protein and modifies it in a way such that it is recognized by a protease whose job it is to recognize and degrade any protein that has been modified by ubiquitin conjugation. As a result, p100 is degraded in the nucleus of the cell and the pathway is cleared and activated, turning on the gene transcription signal.
These new findings lead the researchers to conclude that the intersection of GSK3, Fbxw7α and p100 may serve as a potential intervention point for the treatment of multiple myeloma. Researchers believe if they can find a way to target the elimination of p100 they may be able to inactivate the pathway, which would eliminate the tumor cells' safe haven so that they would be susceptible to apoptosis. This would in turn promote the death of multiple myeloma cells.
According to Dr. Pagano, this strategy may not be too far from becoming a reality. There are already drugs being tested in clinical trials for Alzheimer's Disease that work by inhibiting GSK3. With the current study, the resea
|Contact: Jessica Guenzel|
NYU Langone Medical Center / New York University School of Medicine