"Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1"

In a 2003 publication by Peter Ordentlich, Yingzhuo Yan, Sihong Zhou, and Richard A. Heyman, the role of Agent 6- Mercaptopurine, commonly known as the drug 6-MP, was studied in relation to the protein Nurr1. Nurr1 is encoded by the NR4A2 Gene. 6-MP is used for many diseases, including Crohn's Disease, in an attempt to reduce inflammation. It was demonstrated that the regulation of the transcriptional activity of Nurr1 by 6-Mercaptopurine can be inhibited by certain factors in the purine biosynthesis pathway. This lends to the possibility of Nurr1 interfering with the antiproliferative effects of 6- MP. One of the ways that the specific effects of 6- MP on Nurr1 was tested was by using other nuclear hormone receptors for comparison, specifically LXR, FXR, RXR, ER, and ROR, which did not show activation for up to 50 microM. 

Understanding the receptor function of Nurr1 is critical due to the fact that Nurr1 may lead to the expression of inflammatory hormones. It was also found that the 6-MP effect was not dependent on the ligand-binding domain. 6-MP seemed to be specific to Nurr1 in that other compounds with a similar mechanism do not activate Nurr1. Additionally, it was discovered that the level of adenine, adenosine, or guanosine molecules affect Nurr1. The reduction of adenosine molecules resulted in less of ATP, suggesting that there is an ATP-dependent pathway. When this pathway is blocked, the transcriptional activation occurs. By modifying the mechanism of 6-MP, new findings can be generated on the methods used to regulate Nurr1. 

It is interesting but not surprising that a protein could involve so much complexity in the way of treating diseases such as Crohn's Disease, which can infect the entire gastrointestinal tract in a human body. It is important to try and modify drugs to target certain proteins and therefore possibly result in the expression of particular genes. Crohn's Disease can result in bleeding, pain, and weight loss. 

Links: 

http://www.jbc.org/content/278/27/24791.full.pdf+html?sid=dcdef3a7-3fcc-43e3-8808-fcc7d1719254

http://www.genecards.org/cgi-bin/carddisp.pl?gene=NR4A2

http://www.ccfa.org/resources/maintenance-therapy.html?referrer=https://www.google.com/