The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia.
Rai (Shc C or N-Shc) is a neuron-specific member of the family of Shc-like adaptor proteins. Rai functions in the cytoplasmic propagation of Ret-dependent survival signals and regulates, in vivo, the number of sympathetic neurons. We report here a function of Rai, i.e., the regulation of the neuronal adaptive response to environmental stresses. We demonstrate that (i) primary cultures of cortical neurons from Rai-/- mice are more sensitive to apoptosis induced by hypoxia or oxidative stress; (ii) in Rai-/- mice, ischemia/reperfusion injury induces severe neurological deficits, increased apoptosis and size of the infarct area, and significantly higher mortality; and (iii) Rai functions as a stress-response gene that increases phosphatidylinositol 3-kinase activation and Akt phosphorylation after hypoxic or oxidation insults. These data suggest that Rai has a functional neuroprotective role in brain injury, with possible implications in the treatment of stroke.
Troglio
Flavia
F
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Echart
Cinara
C
Gobbi
Alberto
A
Pawson
Tony
T
Pelicci
Pier Giuseppe
PG
De Simoni
Maria Grazia
MG
Pelicci
Giuliana
G
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004789:Enzyme Activation; D051379:Mice; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3
D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; C485682:Shc3 protein, mouse