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.
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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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