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ROCHESTER, Minn. — April 24, 2014 — Mayo Clinic researchers have uncovered a novel tumor suppressive role for p53, a cancer-critical gene that is mutated in more than half of all cancers found in humans. The researchers found that loss of p53 function caused overproduction of the kinase Aurora A, an enzyme involved in the process of cell division. That overproduction leads to mitotic spindle malformation and aberrant separation of duplicated chromosomes over daughter cells, a phenomenon that predicts tumor metastasis and poor patient outcomes. The findings appear in the journal Nature Cell Biology.
Normal human cells have 46 chromosomes. It has long been recognized that developing cancer cells reshuffle their chromosomes and, more recently, that chromosome-number abnormalities help transform normal cells into cancerous cells that metastasize and resist treatment.
“Attempts to identify which genetic defects drive chromosome reshuffling in human cancer led us to focus on cyclin B1 and B2, two key regulators of the stage in the cell cycle where duplicated chromosomes normally separate,” says Jan van Deursen, Ph.D., Mayo Clinic molecular biologist and principal investigator of the study.
By mimicking cyclin B1 and B2 gene defects observed in treatment-resistant human cancers in mouse models, Hyun-Ja Nam, Ph.D., the lead author of the study, demonstrated that both cyclin B1 and B2 induce chromosome reshuffling and tumor formation. Subsequent studies into the mechanism of action of cyclin B2 pinpointed Aurora A kinase hyperactivity as the main culprit and identified damage or loss of p53 as a mimetic of cyclin B2 gene defects. An important next step will be testing whether anti-cancer drugs that inhibit Aurora A kinase can be effective in treating patients whose tumors have p53 gene defects.
The study was supported by funding from the National Institutes of Health (CA126828).
About Mayo Clinic
Recognizing 150 years of serving humanity in 2014, Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit 150years.mayoclinic.org, www.mayoclinic.org and newsnetwork.mayoclinic.org.
Robert Nellis, Mayo Clinic Public Affairs, 507-284-5005, firstname.lastname@example.org
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