Andrei Thomas Tikhonenko
Investigators have uncovered a novel role for the tumor suppressor p53, according to a paper published in Nature Cell Biology.
The research showed that loss of p53 function caused overproduction of the Aurora A kinase, an enzyme involved in cell division.
That overproduction led to mitotic spindle malformation and aberrant separation of duplicated chromosomes over daughter cells, a phenomenon that predicts tumor metastasis and poor patient outcomes.
“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,” said principal investigator Jan van Deursen, PhD, of the Mayo Clinic in Rochester, Minnesota.
Dr van Deursen and his colleague, Hyun-Ja Nam, PhD, used mouse models to mimic the cyclin B1 and B2 gene defects observed in treatment-resistant human cancers. And the pair discovered that both cyclin B1 and B2 induce chromosome reshuffling and tumor formation.
Subsequent experiments investigating cyclin B2’s mechanism of action pinpointed Aurora A kinase hyperactivity as the main culprit and showed that damage or loss of p53 is a mimetic of cyclin B2 gene defects.
The investigators said the next step for this research will be testing whether anticancer drugs that inhibit Aurora A kinase can be effective in treating cancer patients whose tumors have defects in p53.
