A Waseda University-led research has uncovered the molecular mechanism of how a particular cancer-causing oncogene could trigger an onset of acute myeloid leukemia (AML).
Characterized by symptoms such as fatigue, shortness of breath, and bleeding gums, AML is a type of cancer that begins in the bone marrow and rapidly affects blood due to the rapid growth of leukemia cells.
This abnormality is caused by mutated genes in chromosomes, turning on oncogenes while turning off tumor-suppressing genes. Mutation occurs when chromosomes are not properly replicated during cell division, and unalignment of even one out of the total of 46 chromosomes in a cell causes missegregation.
To prevent such chromosomal abnormalities, a cell precisely controls chromosome distribution to newborn cells with its voltage sensor, which locates the central region of duplicated chromosomes called the centromere and detects whether the attached microtubule is applied right between the force to the kinetochore, a complex protein at the centromere.
"Since discovering the Aurora B kinase (Aurora B) enzyme in 1996, we have found that Aurora B plays an integral role as a voltage sensor by regulating microtubule attachment to the kinetochore for chromosome regulation, and that protein phosphatase 2 (PP2A) also acts as a voltage sensor by controlling chromosome alignment in correlation with Aurora B, "said Professor Yasuhiko Terada of Waseda University in Tokyo. "However, the system is extremely complex, and its molecular mechanism was not well understood."
In their latest study published in the Journal of Cell Biology, Terada's team found that SET / TAF1, a proto-oncogene of AML, also functions as a voltage sensor by fine-tuning the enzyme activities of Aurora B and PP2A. As the three voltage sensors interact with each other, the replicated chromosomes are evenly distributed to new-born cells and prevent chromosome abnormalities.
"Protein encoded by the SET oncogene (SET) maintained Aurora B activity by inhibiting PP2A activity at the centromeres. It was also intriguing to observe that although SET inhibits PP2A activity to allow high Aurora B activity and adjust microtubule attachment when chromosomes. are not aligned, it detaches from the kinetochore and reduces the activity of Aurora B to stabilize the attachment of microtubules to the kinetochore when the chromosomes are aligned, Terada explained.
Additionally, experiments using molecular biological techniques investigated the oncogenic function of SET to study whether centromere localization of SET is essential for chromosomal abnormality. The results showed that SET disrupts the voltage sensor mechanism at the centromere, supporting previous research that reports how abnormal Aurora B activity is observed in many cancer cells, and how overexpression of Aurora B in normal cells induces chromosome misalignment.
Although many questions remain unexplained to fully understand the molecular mechanism of voltage sensor, Terada believes this discovery could serve as a baseline for further investigation to elucidate the molecular mechanism of chromosome cancer malignancy and the development of leukemia, as well as create anticancer drugs that target SET and Aurora B.
Materials provided by Waseda University. Note: Content may be edited for style and length.