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In contrary to the common belief that only one
strand of the pre- miRNA is active (usually the 5p one that is the more
abundant) while the second one (miRNA*) is discarded, functional 5p and 3p have
been observed for many miRNAs. Among those miRNAs is miR-34a which is a target
gene of the tumor suppressor p53. In this paper we review the role that
miR-34a-5p and miR-34a-3p play in the signaling pathway of p53 by targeting
overlapping sets of genes (MDM2 and THBS1), where THBS1 is involved in cancer
relevant processes, and MDM2 is linked to p53 and miR-34a by a type 1
incoherent FFL that represent a novel mechanism for accelerating the response
of p53 to external stress signals.
INTRODUCTION
The biogenesis of miRNAs can be summarized as
follows: a primary transcript (pri-miRNA) is first generated by RNA polymerase
II. Then the primary transcript is processed by the microprocessor complex
containing the RNase III enzyme Drosha to an approximate 70-nucleotide
pre-miRNA hairpin (the precursor-miRNA) [2-4]. Pre-miRNAs are subsequently
exported to the cytoplasm by exportin 5 (XPO5) [5,6] where their terminal loops
are excised by the RNase III Dicer to give rise to a double stranded 22 nt stem
composed of 5’ and 3’ strands representing 5p and 3p, respectively. While one
of the two strands (the passenger strand miRNA*) is discarded, the other one
(the guide) miRNA is then embedded into the RISC (RNA Induced Silencing Complex)
to complementary target mRNA for post-transcriptional gene silencing [7]. p53
has been dubbed “guardian of the genome” [8] or gatekeeper [9] due to its
central role in maintaining the genomic stability and tumor suppression
[10-12]. It has been found to be mutated in about half of the human cancers
[13,14]. Since its discovery p53 has been subject to a tremendous amount of
work making it one of the most extensively studied gene. Its tumor suppressive
role consists in inducing anti-proliferative cellular responses to a variety of
stress signals, namely a cell-cycle arrest, senescence or an apoptosis. p53 can
then be activated in response to DNA damage, hypoxia or aberrant growth signals
resulting from deregulated expression of oncogenes [15-17].
miRNAs have been shown to be important
components in the p53 network Their interactions with p53 have been
demonstrated through the identification of several miRNAs as direct target
genes of p53. By inducing the expression of specific miRNAs that have a tumor
suppressive function a novel mechanism for tumor suppression for p53 has been
then revealed. In particular the role of the miR-34 family has been reported in
several studies [18].
miR-34 FAMILY AND
THE p53 PATHWAY
Since it was believed that according to the
thermodynamic stability of the pre-miRNA cells preferentially select the less
stable one of the two strands (the guide) and destroy the other one (the
miRNA*), early works on miRNAs have focused on the guide strand (which was
usually considered as the 5p one because it was found to be more abundant than
its counterpart miRNA* in humans [19]). However, even though miRNA* are less
abundant they are often present and remain functional because they conserve
their seed sequences and have been isolated from RISC [20,21]. The interplay between the 5p and
3p strands from
the same
In mammalians miR-34 family consists of
miR-34a, miR-34b and miR-34c that are encoded by two different genes. miR-34a
is encoded by an individual transcript in chromosome 1 and expressed in a
majority of tissues, while miR-34b and miR-34c share a common primary
transcript in chromosome 11 and are mainly expressed in lung tis- sues. Several
studies have reported that the members of miR-34 family were direct target
genes of p53 and their up regulation induces apoptosis and cell-cycle arrest
[27-33]. Indeed, Ectopic expression of miR-34 induces cell cycle arrest in both
primary and tumor-derived cell lines [33]. Inactivation of miR-34a strongly
attenuates p53-mediated apoptosis in cells exposed to genotoxic stress [29].
miR-34b/miR-34c were also down-regulated in p53-null human ovarian carcinoma
cells and both cooperate in suppressing proliferation of neoplastic epithelial
ovarian cells [28]. Since cell-cycle arrest and apoptosis are the responses of
p53 to the stress signals, these facts imply that miR-34 mediate the tumor
suppressive functions of p53. On the other hand the members of the miR-34
family can have decreased expression in cancer because of the inactivating
mutations of p53 or the expression of viral inhibitors of p53, but also as a
consequence of their own mutational or epigenetic inactivation.
Since 30% of all genes and the majority of
the genetic pathways are regulated by miRNAs [12,34,35], we can expect some
miRNAs to regulate p53 and its pathway. This hypothesis has been verified and
some miRNAs have been identified as regulators of p53. Furthermore, miR-34a, which
is a transcription target of the p53 protein, was also found to positively
regulate p53 activity and function in apoptosis through its direct negative
regulation of SIRT1 [36]. SIRT1 is a negative regulator of p53, which
physically interacts with p53 and deacetylates Lys382 of p53 [37].
THE ROLE OF THE
COMMON TARGET GENES MDM2 AND THBS1
We begin by using DIANA-miRPath v3. 0 which
is a miRNA pathway analysis web-server, providing accurate statistics utilizing
predicted or experimentally validated miRNA interactions derived from
DIANA-TarBase [38]. In the p53 signaling pathway we obtain the target genes of
the different miRNAs that we found. Then we use the cytoscape 3.4.0 software to
visualize the interactions where the relevant genes are involved, by taking the
IntAct 1 to be our source of interactions.
For miR-34a the list of target genes contains
30 genes for miR-34a-5p and two for miR-34a-3p (MDM2 and THBS1) that are also
target genes of the miR-34a-5p.
By loading the list of the 30 target genes of
miR-34a-5p (containing also the two targets of miR-34a-3p) in Cytoscape 3.4.0
and searching the interaction in IntAct we obtain a network composed of 2492
nodes and 6493 edges.
In order to find the pathways in which the
THBS1 gene is involved we use the BINGO application of Cytoscape and the
relevant GO terms that are overexpressed in cluster containing the THBS1 gene.
According to this analysis we can deduce that the THBS1 gene is involved in
regulating tumor suppression processes.
MDM2 and p53 are linked by a negative
feedback loop. However, since MDM2 is a target gene of miR-34a which means that
it is negatively regulated by this miRNA, we can represent the interaction
between the three molecules (p53, MDM2 and miR-34a) as a Feed For- ward Loop
(FFL). According to the signs of the three interactions (activation/repression)
the present loop is a type 1 incoherent FFL 1 IntAct is one of the largest
available repositories for curated molecular interactions data, storing PPIs as
well as interactions involving other molecules. It is hosted by the European
Bioinformatics Institute. IntAct has evolved into a multisource curation
platform and many other databases curate into IntAct and make their data
available through it [21].
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