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Kaya et al. Neuroimmunol Neuroinflammation 2019;6:5 I http://dx.doi.org/10.20517/2347-8659.2018.70 Page 11 of 15

of p53 on ERK/MAPK and PI3K/AKT pathways, and thus prevented apoptosis in degenerating hippocampal
and ALS motor neurons. Hence, it is worthwhile to further explore p53-dependent anti-apoptotic regulatory
function of Speedy/RINGO on these pathways.

Our laboratory is currently investigating the function of Speedy/RINGO on the ERK/MAPK and PI3K/
AKT pathways using undifferentiated p53- and Speedy/RINGO-expressing neuronal-like neuroblastoma
cells. Preliminary data give remarkable clues indicating that Speedy/RINGO plays an essential role on the
regulation of ERK/MAPK and PI3K/AKT signaling pathways that directly affect the apoptotic state and
survival rate of neuroblastoma cells. More precisely, silencing of the Speedy/RINGO gene significantly
alters expression levels and phosphorylation states of certain members of the ERK/MAPK and PI3K/AKT
pathways. This, in turn, leads to apoptotic death of neuroblastoma cells, likely due to the absence of Speedy/
RINGO’s regulatory function on these two pathways.

CONCLUSION
SCI is a critical clinical issue whose ongoing destructive path affects patients for life. It is one of the most
important causes of disability and mortality around the world [106,107] .

2+
It has long been known that glutamate-induced Ca influx through glutamate receptors, known as
glutamate excitotoxicity, is indispensable for SCI. This influx ultimately causes the p53-mediated apoptotic
death of neurons. It is most likely that p53 exerts its apoptotic function on the members of ERK/MAPK and
[11]
PI3K/AKT signaling cascades .

2+
The goal of our laboratory is to elucidate and prevent the pro-apoptotic intracellular Ca deregulation in
neurons. We are therefore optimistic about Speedy/RINGO, a novel cell cycle regulatory protein proven to
[12]
have a p53-dependent anti-apoptotic function in different cell types, including U2OS osteosarcoma cells
[13]
as well as calpain-induced degenerating primary hippocampal neurons . In addition, Speedy/RINGO
expression levels were shown to be substantially decreased in ALS motor neurons compared with wild-type
[14]
controls . By contrast, increased Speedy/RINGO expression enhanced cell viability and prevented the DNA
damage response in ALS motor neurons. These findings indicate that Speedy/RINGO plays a protective role
in both ALS motor neurons and in degenerating primary hippocampal neurons. This implies a potential
therapeutic role for oncogenic proteins in neurodegenerative conditions such as SCI.

Although the mechanism of Speedy/RINGO’s anti-apoptotic function in degenerating neurons is not yet
known, Speedy/RINGO most probably exhibits its protective function on downstream targets of p53,
[13]
rather than on p53 levels directly . ERK/MAPK and PI3K/AKT survival pathways are the most important
downstream targets of p53 in cases of neurodegeneration, and Speedy/RINGO has been shown to act on
both pathways. This evidence has come from both cancer studies [16-18] and studies on glial scar formation in
[63]
SCI . Exploring this interaction and revealing the possible regulatory function of Speedy/RINGO on these
pathways may help to someday reverse the p53-induced apoptotic effect observed in SCI.

Overexpressing Speedy/RINGO in in vitro and in vivo SCI models and exploring its effects will provide
important insights about underlying molecular mechanisms of secondary injury. One goal is to study
the abnormal regulation of ERK/MAPK and PI3K/AKT pathways by transcription factor p53, one of the
primary initiators of secondary injury.

As described elsewhere in this paper, we believe that Speedy/RINGO is likely to exhibit anti-apoptotic
activity in the neuron and glia cells of areas affected by SCI, making this protein a strong potential candidate
for therapeutic treatment of SCI patients. In order to confirm the presumed anti-apoptotic function of
Speedy/RINGO in SCI, further studies should be performed with both in vivo and in vitro SCI models.