A role of P301L tau mutant in anti-apoptotic gene expression, cell cycle and apoptosis.
In exploring the causative role of the most common Pro(301)-to-Leu (TauP301L) tau missense mutation associated with neurodegenerative tauopathies, we examined TauP301L-mediated apoptotic cell death and the expression of a cluster of genes involved in the inhibition of apoptosis (IAPs) in human neuroblastoma SH-SY5Y cells. Our research found that the expression of TauP301L, but not wild-type tau, down regulated the expression of IAPs, including survivin, which plays a role in the mitotic spindle checkpoint. The inhibition of IAPs coincided with the activation of the pro-apoptotic caspase 3, but preceded apoptotic cell death by TUNEL. Furthermore, TauP301L altered the expression of the cell cycle regulatory proteins and induced the cell cycle arrest at G(2)/M phase. Our studies demonstrate that TauP301L downregulates the expression of genes that protect against apoptosis and regulate cell cycle progression. These results suggest a novel mechanism of apoptotic cell death in TauP301L-expressing cells that involves survivin-mediated activation of cell cycle checkpoint.
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Neuroinflammation Research Laboratories of the Department of Psychiatry, Box 1230, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
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Ksiezak-Reding
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D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007930:Leucine / Q000235:genetics; D020125:Mutation, Missense; D011392:Proline / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000502:physiology*
D016875:tau Proteins; D011392:Proline; D007930:Leucine