Biology Reference
In-Depth Information
repeat sequences revealed significant global
hypoediting in tumors from brain, prostate, lung, kidney, and testis (Paz
Analysis of editing of
Alu
,
2007). In addition, they observed a reduction in RNA levels of ADAR-1, -2, and
-3 and overexpression of either ADAR1 or ADAR2 in a glioblastoma cell line
resulted in decreased proliferation. The authors concluded that the loss of editing
enzymes was involved in the pathogenesis of cancer.
ADAR activity was also found to be reduced in pediatric astrocytomas
et al.
(Cenci
, 2008). The editing level also correlated with the grade of
malignancy such that high-grade tumors had the lowest levels of editing.
In tumor-derived astrocytoma cell lines, the low level of editing was restored
by overexpression of ADAR2, and this inhibited proliferation in these cell lines.
Although there was no difference in ADAR2 expression between tumor and
control samples, both ADAR1 and ADAR3 were significantly over-expressed in
the astrocytomas. This unbalanced expression could down-regulate ADAR2
activity as when the expression of ADAR1 was increased this led to decreased
editing of ADAR2 substrates in HEK293 cell line. ADAR1 and ADAR2 were
shown to co-immunoprecipitate indicating they could form heterodimers and
the authors propose that a correct balance between ADAR1 and ADAR2 is
required for their specific editing activity (Cenci
et al.
et al.
, 2008).
XIII. ADAR2 PROTECTS AGAINST NEURONAL DEGENERATION
FOLLOWING ISCHEMIC INSULT
Following transient global ischemia, hippocampal CA1 pyramidal neurons de-
generate, while neurons in other regions of the hippocampus remain undamaged.
It was found that the CA1 pyramidal neurons have an 18-fold increased perme-
ability to calcium following ischemic insult (Liu
, 2004). It is unclear what
causes the increased calcium permeability and the specific vulnerability of these
neuronal subset and not others. ADAR2 has recently been implicated in recov-
ery from forebrain ischemia. It was found that expression of
et al.
encoding
the edited isoform that is calcium impermeable in the hippocampus of adult rats
in vivo
GluR-B(R)
rescued vulnerable CA1 pyramidal neurons from forebrain ischemic
injury. However, expressing the unedited calcium permeable isoform GluR-
B(Q) resulted in postischemic degeneration of hippocampal granule neurons
that are normally insensitive to ischemia. It was hypothesized that ADAR2
editing of
is disrupted in CA1 pyramidal neurons following ischemic
insult, and this leads to an influx of calcium which results in neuronal degenera-
tion. In support of this hypothesis, Peng and colleagues showed that siRNA
knockdown of
GluR-B Q/R
in the dentate gyrus increased the sensitivity of neurons to
ischemic insult (Peng
Adar2
et al.
, 2006). This led to decreased editing at the
GluR-B
Q/R
site, which increased AMPA receptor calcium permeability and resulted in
