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Page 10 of 15 Kaya et al. Neuroimmunol Neuroinflammation 2019;6:5 I http://dx.doi.org/10.20517/2347-8659.2018.70

Figure 3. A schematic diagram for the proposed mechanism of anti-apoptotic action of Speedy/rapid inducer of G2/M progression in
oocytes (Speedy/RINGO) on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase and phosphoinositide
3-kinase/protein kinase B (AKT) signaling cascades in degenerating neurons

Evidently, ERK/MAPK and PI3K/AKT signaling is very important for cell survival. Depending on the
cellular context, cell type, and internal/external stimuli, however, p53 may act as a strong anti-apoptotic or
pro-apoptotic regulator of both pathways.

Potential regulatory function of Speedy/RINGO protein on ERK/MAPK and PI3K/AKT pathways
as an inhibitor of apoptosis
Previous investigations by our lab indicate that Speedy/RINGO protects neurons against calpain-mediated
p53-dependent apoptosis without decreasing p53 levels. This finding strongly implies that the anti-apoptotic
effect of Speedy/RINGO is downstream of p53 activation, not directly on calpain or p53 itself. As explained
above, the most remarkable downstream targets of p53, in terms of generating an apoptotic effect on
neurons, are ERK/MAPK and PI3K/AKT pathways. Therefore, in degenerating neurons, Speedy/RINGO
may use its ability to regulate ERK/MAPK and PI3K/AKT pathways to reverse the apoptosis-triggering effect
of p53 induction on these pathways [Figure 3].

Furthermore, cancer studies show promising evidence of direct or indirect interaction of Speedy/RINGO
with ERK/MAP and PI3K/AKT pathways. Several studies on tumorigenesis in breast tissue show that ERK/
MAPK pathway overactivation results in Speedy/RINGO overexpression. As a result of inhibition of enzyme
[16]
MEK1, a member of the MAPK pathway, Speedy/RINGO expression is shown to decrease .
In addition, studies using testis tissue revealed that Speedy/RINGO overexpression causes an increase in
[17]
Cyclin A2-cdk2 expression . Mouse embryonic stem cell studies indicated that Cyclin A2-cdk2 complex
has an important role in AKT hyperphosphorylation, which is a highly effective apoptosis-prevention factor
[18]
in many types of cancer .

On the other hand, studies on glial scar formation through astrocytic gliosis, a hallmark of secondary injury
that inhibits axonal regeneration , show that increased Speedy/RINGO expression is one of the major
[62]
[15]
events responsible for astrocytic proliferation . Since glial scar formation is a very potent inhibitor of SCI
recovery, researchers are studying how to therapeutically prevent astrocytic gliosis. In one of these studies,
[63]
researchers focused on the mitogenic ERK/MAPK signaling cascade in astrocytic proliferation . Their
experimental results showed that ERK/MAPK phosphorylation/activation was increased in proliferating
astrocytes of SCI lesions. Treating these cells with the IFN-β gene significantly reduced ERK/MAPK activity
and the astrocytic proliferation rate.

Findings from these studies on astrocytic gliosis imply that there may be an interaction between upregulation
of Speedy/RINGO and ERK/MAPK hyper-phosphorylation leading to glial scar formation. Taking these
data into consideration, it is reasonable to think that Speedy/RINGO may have reversed the inhibitory effect