Normally, Mcl-1 keeps cells alive by protecting them against apoptosis. For a cell to die, Mcl-1 has to be disabled. “It’s just like a guardian,?Dr. Zhong said.
A healthy organism needs just the right amount of Mcl-1. Too little Mcl-1 can lead to a damaged immune system or even death. Too much, and cells stay alive when they shouldn’t, leading to cancers such as lymphomas.
Using human cell extracts, the researchers found that Mule caused a protein called ubiquitin to bind to several sites on Mcl-1. When ubiquitin binds to a molecule, it serves as a flag for that molecule to be destroyed.
“If you have too much Mule in a cell, Mcl-1 will degrade tremendously,?Dr. Zhong said.
The search for Mule took more than two years, as the UT Southwestern researchers specifically searched for an enzyme that controls Mcl-1.
The interaction between Mule and Mcl-1 might someday be manipulated to help cancer patients, Dr. Wang said. For instance, a tumor may contain cells with a deficit of Mule, making the tumor more likely to grow and perhaps be resistant to chemotherapy. Treatment might then focus on the biochemistry of Mule and Mcl-1, he said.
“We might be able to see if there’s a problem with Mule, or perhaps we could screen beforehand,?Dr. Wang said.
Other UT Southwestern researchers involved in the study were Wenhua Gao, student research assistant, and Dr. Fenghe Du, research specialist.
The work was supported by the Howard Hughes Medical Institute, the National Institutes of Health and The Welch Foundation.