Modulation of mRNA Activity Regulates Thrombin Synthesis

A paper described the molecular mechanism that regulates synthesis of thrombin, a protein required for blood clotting but also implicated in processes related to inflammation and tumor metastasis.

Thrombin is a key protease involved in blood coagulation, complement activation, inflammation, angiogenesis, and tumor invasion. While prothrombin production increases when an organism experiences stress, the molecular pathways controlling this process have not been defined. Now, in a paper published in the February 4, 2011, issue of the journal Molecular Cell, investigators at the European Molecular Biology Laboratory (Heidelberg, Germany) have found that prothrombin expression is regulated by a posttranscriptional regulatory mechanism responding to stress and inflammation.

This mechanism is triggered by external stimuli that activate p38 MAPK (p38 mitogen-activated protein kinase), one of the class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis.

The activated p38 MAPK stimulates enzymes responsible for manipulating the 3′ end of certain classes of mRNA and phosphorylates the RNA-binding proteins FBP2 and FBP3, which inhibit 3′ end processing of mRNAs. By blocking this inhibitor, p38 MAPK removes an obstacle to thrombin synthesis, and the level of thrombin in the blood increases.

While elevated thrombin production is beneficial to an organism under stress, analysis of liver samples taken from septicemic mice and from cancer patients, revealed that thrombin production increased in response both to widespread inflammation during septicemia and to localized inflammation at the tumor's invasion front.

"Knowing the exact molecules involved, and how they act, has implications for treatment, especially as drugs that inhibit p38 MAPK are already being tested in clinical studies for other conditions,” said contributing author Dr. Matthias Hentze, associate director of the European Molecular Biology Laboratory. Those drugs could be good candidates for potential cancer or septicemia therapies.”

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European Molecular Biology Laboratory