Biology Reference
In-Depth Information
LIN-28
let-7
let-7 targets
Undifferentiated
self-renewing cells
Differentiated cells
Figure 1.8
Regulation of cellular differentiation by let-7. Many types of self-renewing
cells, such as embryonic stem cells and tumor cells, express high levels of LIN-28 and
other targets of let-7 regulation that promote cell division. When cells are induced to
differentiate, levels of these genes drop as let-7 expression increases, resulting in relatively
high levels of let-7 in most differentiated cell types and repressed cell division programs.
pattern seems to be largely accomplished by LIN28, which is abundant in
ESCs (
Viswanathan and Daley, 2010
). As described above, the LIN28 protein
inhibits the accumulation of mature let-7, thus preventing cellular differentia-
tion pathways. During stem cell differentiation, miR-125 and let-7 down-
regulate expression of LIN28 through complementary sites in its 3
0
UTR
(
Rybak
et al.
, 2008; Wu and Belasco, 2005
). Thus, let-7 promotes its own
expression by targeting its negative regulator LIN28. Given that let-7 is widely
expressed in most somatic tissues, the role of LIN28 in inducing pluripotent
stem (iPS) cells from fibroblasts may depend largely on its ability to repress let-7
and, thus, differentiation pathways. Additionally, aberrant activation of LIN28
occurs in some tumors, resulting in downregulation of let-7 and its ability to
repress targets that promote cell division (
Viswanathan and Daley, 2010
).
The default pathway for ESCs depleted of miRNA processing factors is
self-renewal (
Kanellopoulou
et al.
, 2005; Murchison
et al.
, 2005; Wang
et al.
, 2007
). However, introduction of mature let-7 miRNAs into such
cells results in silencing of the self-renewal program, demonstrating the
potent ability of these miRNAs to inhibit stem cell properties (
Melton
and Blelloch, 2010
). This effect is not observed in normal ESCs because
an opposing set of miRNAs is sufficient to maintain the self-renewal
properties in the presence of let-7. Given the fundamental role of let-7 in
promoting differentiation pathways, it is perhaps not surprising that inhibi-
tion of these miRNAs in mouse fibroblasts enhances the ability of repro-
gramming factors to produce iPS cells (
Melton and Blelloch, 2010
).
4.2. Cancer
Cancer results when cells fail to either differentiate properly or acquire the
ability to self-renew, like stem cells. In many cases, this requires the activa-
tion of genes repressed by let-7 miRNAs. This
is accomplished by
