They found that preventing the activity of miR-451 produced only modest effectsmild anemia in the micebut when the team subjected mice to oxidant stress by dosing them with a drug that produces free radicals, the mice had profound anemia. The oxygen radicals attacked hemoglobin, the iron-carrying molecule in red blood cells.
"This is a common theme in microRNAsfrequently, they don't play a central role during tissue formation or normal conditions, but they have a strong protective effect when an organism is stressed," said Weiss. "Over evolutionary time, red blood cells have evolved ways to protect themselves; one of those ways is the action of microRNA."
Weiss's team found that miR-451, acting through intermediate steps on a signaling pathway, affects a key protein, FoxO3. As a transcription factor, FoxO3 regulates hundreds of genes; in this case, FoxO3 stimulates specific genes that protect red blood cells from oxidant stress. The knockout mice in this study, having lost miR-451's function, showed impaired FoxO3 activity, and less ability to protect their red blood cells.
The regulatory pathway seen here, Weiss added, may have medical implications beyond blood cell development. "This finding does not have immediate clinical application for patients with blood diseases, but it sheds light on how microRNAs fine tune physiological functions in different contexts," said Weiss. FoxO3 regulates anti-oxidant functions in heart cells and also acts as a tumor suppressor, so miR-451 may have an important role in heart protection and in fighting cancers. "Further studies may broaden our knowledge of how this microRNA may defend the body against disease," he added.
|Contact: John Ascenzi|
Children's Hospital of Philadelphia