FAT10 to MAD2, do you copy? NMR clues to inflammatory cancer

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  • Published: Mar 1, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: FAT10 to MAD2, do you copy? NMR clues to inflammatory cancer

FAT10 to MAD2, do you copy?

The interaction between two proteins, FAT10 and MAD2, leads to cancers associated with inflammation, including liver (hepatocellular carcinoma) and colorectal cancers. NMR spectroscopy reveals new clues regarding the structure of FAT10 and might lead to innovative ways to disrupt this unique interaction and perhaps inhibit cancer. Credit: Caroline G. Lee et al/PNAS

The interaction between two proteins, FAT10 and MAD2, leads to cancers associated with inflammation, including liver (hepatocellular carcinoma) and colorectal cancers. NMR spectroscopy reveals new clues regarding the structure of FAT10 and might lead to innovative ways to disrupt this unique interaction and perhaps inhibit cancer.

A research team led by Caroline Lee of the National University of Singapore (NUS), National Cancer Centre and Duke-NUS, working with Song Jianxing, has developed a new approach to fighting cancer. They have demonstrated a connection between two proteins, FAT10 and MAD2, and cancer. FAT10 is a ubiquitin-like modifier protein and is encoded in Chromosome 6 next to the immune system's major histocompatibility complex (MHC) cluster of genes. It is made in the spleen and thymus and is activated by the joint efforts of tumour necrosis factor alpha and gamma interferon, and so is connected with the inflammatory response. MAD2, mitotic arrest deficient 2, is a spindle checkpoint protein that helps to ensure that the chromosomes are properly attached before separation starts in cell division.

The discovery of a connection between these two proteins might underpin the development of cancer linked to inflammation and so open up new targets for the design of pharmaceuticals that target the specific interaction without affecting other vital cellular functions and so reduce possible side effects. The team provides details in the journal Proceedings of the National Academy of Sciences.

Overexpression

Lee and colleagues previously demonstrated that overexpression of FAT10 can lead to tumour formation, growth and progression. But, what the mechanism underlying this promalignant character was not clear. They have now found that when FAT10 interacts with MAD2 it disrupts that protein's checkpoint functions, leading to cells dividing with abnormal numbers of chromosomes, which can give rise to cancer cell formation if those abnormal cells persist in the body without themselves being checked by immune activity. NMR allowed them to determine the three-dimensional structures of FAT10 and the nature of the interaction between the two proteins.

Mutation manipulation

Experiments using genetic mutation manipulation, also showed them that if this errant interaction between FAT10 and MAD2 is itself disrupted, the number of chromosomes in the affected cells is restored and tumour progression is curtailed, without affecting FAT10’s interaction with its other known key interaction partners. This, they suggest, offers an entirely new paradigm for pharmaceutical intervention in inflammatory cancers. A novel small molecule anticancer drug that can inhibit the interaction between FAT10 and MAD2 would preclude tumour formation in that context. The team is now scouting for likely lead compounds for drug discovery.

"Many current strategies target over-expressed genes to inhibit their expression," explains Lee. "As these cellular genes perform other functions besides causing cancer, inhibiting their expression in a blanket fashion may result in undesirable side effects as the physiological function of these genes may be affected as well. Our strategy works differently as it targets a specific pathological function of the 'culprit' molecule without affecting its other physiological functions. This is especially important for a molecule like FAT10 which is not only over-expressed during cancer formation but is also over-expressed during immune response."

"We are in the process of identifying small molecules that can interfere with the binding between FAT10 and MAD2," Lee told SpectroscopyNOW.

Related Links

Proc Natl Acad Sci 2015, online: "Disruption of FAT10–MAD2 binding inhibits tumor progression"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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