PTEN: A crucial mediator of mitochondria-dependent apoptosis |
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Authors: | Y Zhu P Hoell B Ahlemeyer J Krieglstein |
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Institution: | 1. Institut für Pharmakologie und Toxikologie, Philipps-Universit?t Marburg, D-35032, Marburg, Germany 3. Department of Neurosurgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany 2. Institut für Anatomie und Zellbiologie, Justus-Liebig-Universit?t Giessen, D-35385, Giessen, Germany
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Abstract: | The highly frequent mutation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in various cancers has attracted
much attention to study its role in tumorigenesis. As an important tumor suppressor, the pro-apoptotic function of PTEN has
been linked to its capacity antagonizing the PI3K/Akt signaling pathway. However, less data are available concerning its role
in neurodegeneration in which apoptotic processes are also involved. In the present study, we attempted to study the role
and the underlying mechanism of PTEN in neuronal apoptosis. Using primary rat hippocampal cultures, staurosporine (STS, 100 nM)
induced a time-dependent apoptosis, accompanied by a marked production of reactive oxygen species (ROS), release of cytochrome
c and activation of caspase 9 and 3. However, the expression of PTEN, and the levels of phospho-PTEN and phospho-Akt were not
changed at all time points tested (0.5–24 h) after STS stimulation, suggesting that the protein level as well as the phosphorylation
status of PTEN were not related to the procession of apoptosis. Interestingly, immunostaining revealed a punctate intracellular
distribution of PTEN from 2 to 8 h after adding STS. Double labeling and Western blotting of mitochondrial fraction demonstrated
a mitochondrial location and accumulation of PTEN, respectively, after challenging with STS. Furthermore, we provide evidence
for the first time that PTEN was associated with Bax in the absence and the presence of STS. Of note, the STS-induced marked
increase in the cellular ROS level, release of cytochrome c and activation of caspase 3 were inhibited in cultured hippocampal cells when PTEN was knocked down by a specific antisense.
Moreover, knockdown of PTEN significantly protected hippocampal cells from apoptotic damage. These findings demonstrated that
PTEN is a crucial mediator of mitochondria-dependent apoptosis, and thus could become a molecular target for interfering with
neurodegenerative diseases. |
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Keywords: | mitochondria neuronal apoptosis PTEN ROS rat primary hippocampal culture staurosporine |
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