MicroRNAs link the
pathways that control growth during animal development and in disease
Cellular
mechanisms that enable healthy growth can spiral out of control and give rise
to cancer. For this reason, signal transduction pathways that underlie cell
growth are tightly regulated, with multiple checkpoints and extensive
cross-talk in between signal cascades that drive cell division and
differentiation. Stephen Cohen and co-workers at the A*STAR Institute of
Molecular and Cell Biology1 have identified a new link between growth
controlling microRNAs and this cellular circuitry.
MicroRNAs
(miRNAs) bind complementary nucleotide sequences on specific target messenger
RNA molecules to suppress their expression of proteins. One of these miRNAs,
bantam, is known to regulate cell proliferation and survival. Cohen and
co-workers set out to determine how this molecule contributes to tissue
development in fruit flies.
Growth
control pathways are often complicated. The epidermal growth factor (EGF)
signaling pathway is important in growth control and in cancer, EGF receptor
(EGFR) sends signals into cells that control many aspects of cellular function,
including gene expression. One of the ways EGFR signals is by reducing
expression of capicua, a protein that inhibits other growth-promoting genes.
When
Cohen and his team experimentally reduced capicua levels, they observed a boost
in bantam expression, flagging bantam as a target of capicua-mediated
inhibition. More importantly, they learned that bantam in turn feeds back to
inhibit expression of capicua. The end result is a negative feedback loop that
can accelerate the activation or inactivation of EGFR-mediated growth signals —
for example, as bantam level rises, capicua level drops, and then bantam level
rises even faster to promote cell growth.
The
researchers also uncovered an additional layer of complexity in the story. They
have previously found that a separate growth regulatory and cancer pathway,
triggered by the protein Hippo, also modulates the level of bantam. This places
bantam as a link between the Hippo and EGFR pathways; that is, a microRNA could
mediate the flow of information between these pathways, so that each can
influence the ‘effectiveness’ of the other.
“Regulation
of bantam by both EGFR and Hippo reveals an unexpected link between these two
growth-regulatory pathways,” explains Cohen. “EGFR activity can change
sensitivity to Hippo activity, and vice versa.”
A
better understanding of the connections between these pathways could illuminate
potential triggers for tumorigenesis, although the connection between fly and
human is not a straight line. “The bantam–capicua connection is not conserved
in humans,” explains Cohen. “However, we have identified other new growth
regulatory targets of bantam and are now studying their roles as tumor
suppressors.”
The A*STAR-affiliated researchers contributing to this
research are from the Institute
of Molecular and Cell Biology
References
- Herranz, H., Hong, X. & Cohen, S. M. Mutual repression by bantam miRNA
and Capicua links the EGFR/MAPK and Hippo pathways in growth
control. Current Biology 22, 1–7 (2012). | article
No comments:
Post a Comment