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Published online March 12, 2007
doi:10.1083/jcb.200608022
The Journal of Cell Biology, Vol. 176, No. 6, 853-862
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Ueda et al.
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Identification of prothymosin-{alpha}1, the necrosis–apoptosis switch molecule in cortical neuronal cultures



Hiroshi Ueda, Ryousuke Fujita, Akira Yoshida, Hayato Matsunaga, and Mutsumi Ueda

Division of Molecular Pharmacology and Neuroscience, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan

Correspondence to Hiroshi Ueda: ueda{at}nagasaki-u.ac.jp

We initially identified a nuclear protein, prothymosin-{alpha}1 (ProT{alpha}), as a key protein inhibiting necrosis by subjecting conditioned media from serum-free cultures of cortical neurons to a few chromatography steps. ProT{alpha} 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 Bcl2-family proteins. The apoptosis caused by ProT{alpha} was further inhibited by growth factors, including brain-derived neurotrophic factor. The ProT{alpha}-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 PKCßII expression prevented this cell death mode switch. Collectively, these results suggest that ProT{alpha} 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.

Abbreviations used in this paper: AS-ODN, antisense ODN; BDNF, brain-derived neurotrophic factor; CM, conditioned medium; HD, high-density; LD, low-density; LOG, low-oxygen and low-glucose; MALDI-TOF, matrix-assisted laser desorption/ionization–time of flight; MS, mass spectrometry; ODN, oligodeoxynucleotide; PI, propidium iodide; ProT{alpha}, prothymosin-{alpha}1.


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