Identification of prothymosin-alpha1, the necrosis-apoptosis switch molecule in cortical neuronal cultures.
We initially identified a nuclear protein, prothymosin-alpha1 (ProTalpha), as a key protein inhibiting necrosis by subjecting conditioned media from serum-free cultures of cortical neurons to a few chromatography steps. ProTalpha inhibited necrosis of cultured neurons by preventing rapid loss of cellular adenosine triphosphate levels by reversing the decreased membrane localization of glucose transporters but caused apoptosis through up-regulation of proapoptotic Bcl(2)-family proteins. The apoptosis caused by ProTalpha was further inhibited by growth factors, including brain-derived neurotrophic factor. The ProTalpha-induced cell death mode switch from necrosis to apoptosis was also reproduced in experimental ischemia-reperfusion culture experiments, although the apoptosis level was markedly reduced, possibly because of the presence of growth factors in the reperfused serum. Knock down of PKCbeta(II) expression prevented this cell death mode switch. Collectively, these results suggest that ProTalpha is an extracellular signal protein that acts as a cell death mode switch and could be a promising candidate for preventing brain strokes with the help of known apoptosis inhibitors.
Ueda
Hiroshi
H
Division of Molecular Pharmacology and Neuroscience, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp
Fujita
Ryousuke
R
Yoshida
Akira
A
Matsunaga
Hayato
H
Ueda
Mutsumi
M
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D017077:Culture Media, Conditioned; D008969:Molecular Sequence Data; D009336:Necrosis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D051381:Rats; D013947:Thymosin / Q000031:analogs & derivatives* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology
D017077:Culture Media, Conditioned; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin