Biology Reference
In-Depth Information
miR-98/miR-4458/miR-4500- or the miR-30
miRNA family exist. They consist out of several
different members, which all have the same seed
sequence, that is, nucleotides 2 to 8 from the 5
0
end of the miRNA. The seed sequence is the
site of the miRNA, which usually hybridizes
perfectly with the mRNA and it is thought that
miRNAs with the same seed sequence usually
target the same mRNAs. High similarity of
miRNA family members might pose problems
when analyzing individual family members, as
highly related miRNAs are dif
in virtually all forms of cancer. The miRNA
expression pro
les differ between normal tissues
and the tumors that are derived from them, and
they also differ between tumor types. The initial
observation that miR-15 and miR-16 dysregula-
tion in many cases of B cell chronic lymphocytic
leukemia is the result of a deletion on chromo-
some 13q14
9
was followed by investigations
showing that miRNAs quite frequently localize
to fragile chromosomal
regions deleted in
several forms of cancer.
10
The concept of tumor suppressor genes and
oncogenes extends tomiRNAgenes (
cult to distin-
guish with several experimental methods. Also,
performing functional studies by, for example,
knocking out miRNA genes in mice can be
tedious, as in some cases no clear phenotype
might be observed and related family members
could potentially compensate for the loss of
one family member. Possibly, a phenotype might
only be visible when several family members
have been deleted simultaneously.
“
”
),
as it has been shown that increased expression of
a certain miRNA might lead to decreased expres-
sion of an miRNA-controlled tumor suppressor
gene or, conversely, that decreased expression
of a certain miRNA can potentially lead to the
overexpression of an oncogene being normally
regulated by this miRNA.
11,12
A selection of
miRNAs and their associated forms of cancer can
be found in
Table 1
.
Not onlymiRNAthemselves, but alsomembers
of the miRNA-processing machinery have mean-
while been shown to be important factors of
cellular transformation and tumor development
(
Table 2
). Tumor-speci
oncomirs
What Is Known about miRNAs in
Health and Disease?
miRNAs regulate mRNAs that encode
proteins, which in turn modulate cellular func-
tions and fate. Although some miRNAs such as
miR-1 in muscle
6
or miR-122 in the liver
7
are
tissue-speci
c genetic defects in the
genes for Exportin-5,
32,33
TRBP
34
or DICER
35,36
could also help to explain the
finding why
miRNAs are mostly downregulated in cancer.
37
In addition to cancer, miRNAs also show
deregulated expression in non-tumor diseases.
These include neurological disorders, such as
miR-206 de
c, most miRNAs show a broader
tissue distribution. Until now, no organ or tissue
has been identi
ed that lacks miRNAs. miRNAs
are thought to function like gene rheostats, which
help to
fine-tune gene expression and also to
confer robustness to complex biological systems.
8
As a consequence, small changes in miRNA
expression can have a big impact on whole gene
regulatory nodes. Although having these small
regulators at hand is on the one hand a convenient
way for the cell to control its metabolism, on the
other hand, the potential deregulation of a single
miRNA can lead to dramatic changes in general
gene expression patterns.
It was therefore not surprising that it was
soon discovered that miRNAs are deregulated
ciency accelerates amyotrophic
lateral sclerosis
38
or cardiovascular disorders;
for example, miR-1 is involved in arrhythmia
and hypertension.
6
Further examples are
covered extensively by some recent reviews.
39,40
How Can miRNAs Be Detected and
Quanti
ed?
Detection and quanti
cation of miRNAs is
due to several reasons not straightforward. For
example, the small size of mature miRNAs of
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