Study shows the importance of a cancer-causing oncogene, known as SET/TAF1, in triggering cancer cell proliferation.
New findings by Waseda University showed the molecular mechanism of how a particular cancer-causing oncogene, known as SET/TAF1, could trigger onset of acute myeloid leukemia (AML).
The proliferation of AML has historically been linked to the rapid growth of leukemia cells caused by mutated genes in chromosomes turning on oncogenes while turning off tumor-suppressing genes.
To prevent a chromosomal abnormality such as missegregation, a cell will control chromosome distribution to the new-born cells with its tension sensor. This sensor locates the central region of the duplicated chromosomes, called the centromere, and detects whether the attached microtubule is applying the right amount of force to the kinetochore, a protein complex at the centromere.
Researchers had previously discovered that the enzyme Aurora B kinase (Aurora B) plays an integral role as a tension sensor by adjusting microtubule attachment to the kinetochore for chromosome regulation and that protein phosphatase 2 (PP2A) also acts as a tension sensor by controlling chromosome alignment in correlation with Aurora B.
In the current study, published in the Journal of Cell Biology, the researchers found that SET/TAF1, a proto-oncogene of AML, also functions as a tension sensor by fine-tuning the enzyme activities of Aurora B and PP2A. As the 3 tension sensors interact, the replicated chromosomes are distributed evenly to the new-born cells and prevent chromosome abnormalities.
Researchers explained that proteins encoded by SET maintained Aurora B activity by inhibiting the PP2A activity at the centromeres. Also, though SET inhibits activity of PP2A to allow a high Aurora B activity and adjust microtubule attachment when chromosomes are not aligned, it detaches from the kinetochore and decreases the activity of Aurora B to stabilize attachment of microtubules to the kinetochore when chromosomes are aligned.
Additionally, experiments using molecular biological techniques to investigate the oncogenic function of SET and whether centromere localization of SET is essential for chromosomal abnormality showed that SET disrupts the tension sensor mechanism at the centromere, supporting previous research that illustrated how abnormal activity of Aurora B is observed in many cancer cells. These experiments also revealed how overexpression of Aurora B in normal cells induce chromosome misalignment.
The researchers believe that this discovery could serve as a baseline for further investigation to elucidate the molecular mechanism of cancer malignancy by chromosome missegregation and the development of leukemia, as well as create anticancer drugs that target SET and Aurora B, according to the study authors.