New Understanding Of How Molecules Regulate An Enzyme Holds Promise

A new understanding of how molecules affect the activity of an enzyme holds promise that could potentially lead to targets for the treatment of neurodegenerative diseases and cancers.

Researchers at the Tohoku University are using cell culture studies along with gene silencing techniques to investigate how molecules regulate the enzyme known as ASK1 called apoptosis signal regulating kinase. Irregular apoptosis signal regulating kinase activation is associated with some cancers, neurodegenerative, and inflammatory diseases.

Apoptosis signal regulating kinase normally will be activated within the body by oxidative stress, which is a process that involves high rates of oxygen metabolism that occurs in the response to stress, infections, and toxins. A variety of molecules are known to regulate apoptosis signal regulating kinase, but how it is done has not been certain.

An enzyme known as PRMT1 called protein arginine methyltransferase is known to encourage apoptosis signal regulating kinase to interact with a small protein known as Trx called thioredoxin, in which the interaction will effectively turn off apoptosis signal regulating kinase, interfering with the enzyme’s role in initiating the cell signalling process that will ultimately lead to inflammation and cell death.

The team found that a protein known as TRIM48 called tripartite motif 48 starts the process which labels protein arginine methyltransferase for destruction within the cells. Protein arginine methyltransferase deficiency basically means that apoptosis signal regulating kinase and thioredoxin aren’t able to interact, which turns on apoptosis signal regulating kinase.

When the team turned off the gene that codes for tripartite motif 48, apoptosis signal regulating kinase failed to be activated by the oxidative stress. When the team made that same gene work excessively in cancer cells planted within mice models, the cancer cell death and the suppression of tumour growth was observed, possibly due to apoptosis signal regulating kinase hyperactivation.

Protein arginine methyltransferase upregulation may be caused by decreased tripartite motif 48 activity or expression leading to cancer progression and development. Future studies will determine whether tripartite motif 48 suppresses the development of cancer and progression through protein arginine methyltransferase down regulation according to the researchers.

Future studies could possibly reveal that the pathways involved in the regulation of apoptosis signal regulating kinase activation may act as therapeutic targets to be used in the treatment of apoptosis signal regulating kinase related diseases.