||Recently, researchers from
the University of Pennsylvania School of Medicine determined
how microRNAs (miRNAs) team up with a regulatory protein
to halt protein production.
||By improving understanding about how
miRNAs control protein synthesis under normal conditions,
the researchers hope to identify how miRNA-mediated gene
expression regulation fails in human diseases.
||Results of the study were published recently
(PHILADELPHIA) – While most RNAs work to create, package,
and transfer proteins as determined by the cell’s immediate
needs, miniature pieces of RNA, called microRNAs (miRNAs) regulate
expression. Recently, researchers from the University
of Pennsylvania School of Medicine determined how miRNAs team up with a regulatory
protein to halt protein production. Results of the study were published
recently in Cell.
Scientists estimate miRNAs have the ability to regulate the expression
of approximately one third of human genes, and previous studies have
linked abnormal activity of miRNAs to cancer and other diseases.
While scientists know that most miRNAs in mammals repress the translation of RNA to protein, the molecular steps by which they achieve regulation are largely unknown. By studying the relationship between human miRNAs
and the regulatory protein Argonaute2 (Ago2), lead author Marianthi
Kiriakidou, MD, Assistant Professor of Medicine, and others set out to uncover how
miRNAs control protein synthesis.
Before interfering with protein production, miRNAs associate with proteins
from the Argonaute (Ago) family. According to Kiriakidou, “Ago
proteins are at the heart of the miRNA regulatory pathway, due to their
engagement with miRNAs.”
The miRNA and Ago protein association dictates the way that miRNA regulates
gene production. While there are four different proteins in the human
Ago family, Kiriakidou and colleagues from Zissimos
focused on the interaction between miRNA and Ago2. Ago2 stands out among
the four mammalian Ago proteins since it is the only Ago protein able
to mediate RNA interference by inhibiting gene expression.
Under normal conditions, the initiation of protein synthesis is kicked
off when a protein called eIF4E binds to the front end, or cap, of messenger
RNA. With eIF4E in place, a cascade of protein-protein and protein-RNA
interactions allows the manufacturing of proteins to begin. However,
the assembly of proteins quickly comes to a standstill when the miRNA-Ago2
complex binds near the back end of a messenger RNA. By analyzing the
amino acid sequence of Ago2, Kiriakidou and others uncovered a similarity
with the cap-binding domain of the EIF4E protein that offered a clue
as to why the miRNA-Ago2 complex blocked protein production.
“When the miRNA-Ago2 complex pairs with a messenger RNA, Ago2
engages the cap of the RNA,” explains Kiriakidou. “We believe
this results in competition with eIF4E and disrupts the normal initiation
process of protein synthesis.”
By improving understanding about how miRNAs control protein synthesis
under normal conditions, the researchers hope to identify how miRNA-mediated
gene expression regulation fails in human diseases.
“Many studies show that miRNAs are differentially expressed in
a wide variety of human cancers and therefore have the potential to be
used as diagnostic biomarkers for cancers,” says Kiriakidou. “Understanding
the central role of Ago2 in the miRNA pathway provides a foundation for
future studies that aim to elucidate the contribution of miRNAs to normal
cellular functions and disease processes.”
Penn co-authors are Grace Tan, Styliani Lamprinaki, Mariangels De Plannell-Saguer,
Peter T. Nelson, and Zissimos Mourelatos.
This work was funded by the National
Institute of Allergy and Infectious Diseases, the National
Institute of General Medical Sciences, The
Philadelphia Foundation, and the McCabe Fund.
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