Pediatric researchers have discovered a new biological pathway in which small segments of RNA, called microRNA, help protect red blood cells from injury caused by chemicals called free radicals. The microRNA seems to have only a modest role when red blood cells experience normal conditions, but steps into action when the cells are threatened by oxidant stress.
Led by hematologist Mitchell Weiss, M.D., Ph.D., of The Children's Hospital of Philadelphia, the current study describes how a particular microRNA fine-tunes gene activity by acting on an unexpected signaling pathway.
The study appears in the August 1 issue of the journal Genes & Development, simultaneously with a similar study of microRNAs and red blood cells by a University of Texas team led by Eric Olson, Ph.D. The two studies reinforce each other, said Weiss.
MicroRNAs are single-stranded molecules of ribonucleic acid (RNA) averaging only 22 nucleotides long. Scientists estimate that 500 to 1000 microRNAs exist in the human genome. First characterized in the early 1990s, they received their current name in 2001. Over the past decade, scientists have increasingly recognized that microRNAs play a crucial role in regulating genes, most typically by attaching to a piece of messenger RNA and blocking it from being translated into a protein, but many details remain to be discovered.
"Although microRNAs affect the formation and function of most or all tissues, for most microRNAs, we don't know their precise mechanisms of action," said Weiss. "In this case we already knew this microRNA, called miR-451, regulates red blood cells in zebrafish and mice, and because it is highly conserved in evolution, we presume it operates in humans as well. But its functional roles were poorly understood."
By investigating how microRNAs influence red blood cell development, Weiss and colleagues aimed to understand how such development goes wrong in hemolytic anemia, in which red blood cells are destroyed in large numbers, or in disorders of abnormal blood cell production. The current study used knockout mice--bioengineered animals in which the miR-451 gene was removed and could not function.
They found that preventing the activity of miR-451 produced only modest effects--mild anemia in the mice--but 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 microRNAs--frequently, 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.
The National Institutes of Health, the Roche Foundation for Anemia Research and the March of Dimes Foundation provided grant support for this study. Weiss's co-authors included Barry H. Paw, M.D., Ph.D., of Brigham and Women's Hospital and Harvard Medical School; Duonan Yu, Camila O. dos Santos, and several other colleagues from The Children's Hospital of Philadelphia; and collaborators from Northwestern University, Chicago; Mount Sinai School of Medicine, New York City; and the Amnis Corporation, Seattle.
"miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta," Genes and Development, published online July 31, 2010, in print issue on Aug. 1, 2010. doi: 10.1101/gad.1942110.
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