Human Neural Stem Cells Genetically Modified to Overexpress Akt1 Provide Neuroprotection and Functional Improvement in Mouse Stroke Model - Genetic Engineering: Recent Developments in Applications - page 304

Akt activity is induced following PI3K activation in various growth factor-
mediated signaling cascades [23]. The PI3K-Akt signal pathway is well-known
for the cell survival and it exhibits anti-apoptotic effects against a variety of apop-
totic paradigms including withdrawal of extracellular signaling factors, oxidative
and osmotic stress, irradiation and ischemic shock [24]-[27]. Akt regulates cell
growth and survival mechanisms via phosphorylation of a large number of sub-
strates such as Forkhead transcription factors (FOXO), GSK-3, BAD, caspase-9
and MDM2, and many of these proteins contribute to antiapoptotic signaling in
various cell types [24]-[27]. Activation of PI3K/Akt signaling pathway promotes
extended survival of neuronal cell types from cell death caused by injuries, includ-
ing cerebellar granule cells [23] and hippocampal neurons [27]-[29].
Akt1 as well as its downstream molecules offer great promise for the develop-
ment of therapeutics against a number of neurological disorders such as stroke,
spinal cord injury and neurodegenerative diseases such as Alzheimer disease, Par-
kinson disease and ALS. Initially believed to have cellular functions directed pri-
marily toward cell survival and growth, Akt1 is now seen as a potential broad
cytoprotective agent. Akt1 can offer cellular protection not only through the
modulation of intrinsic apoptotic machinery, but also through the activation of
survival signal pathways. Akt1 drives cellular survival signals through a series of
distinct pathways that involve the Forkhead family of transcription factors, GSK-
3 β , β -catenin, eIF2B, c-Jun, CREB, Bad, IKK, p53, and JIPs [25], [26]. Yet, it
is evident that further work that clarifies the cellular environment controlled by
Akt1 will be of exceptional value to refine our knowledge of Akt1 and to maxi-
mize the potential of this protein as a therapeutic agent.
Acknowledgements
We thank Dr. Min C. Lee for critical reading and comments of the manuscript.
Author contributions
Conceived and designed the experiments: HJL MKK SUK. Performed the experi-
ments: HJL MKK HJK SUK. Analyzed the data: HJL MKK HJK SUK. Wrote
the paper: HJL SUK.
references
1. Gebel JM, Broderick JP (2000) Intracerebral hemorrhage. Neurol Clin 18:
419-438.