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M. Donovan, T. G. Cotter; Expression of the Pro-Apoptotic Bcl-2 Family Member Bim Is Regulated by Multiple Signaling Pathways During Retinal Development and Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4949.
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Apoptosis is essential for retinal development but is also a central component of many retinal dystrophies The purpose of this study was to investigate the signaling pathways involved in the suppression of the pro-apoptotic Bcl-2 family member Bim following developmental cell death in the retina. Additionally, the signals leading to its re-expression during apoptosis induced by several death stimuli are also explored.
Cell death was analyzed by TUNEL during postnatal development in wild type and Bim-/- mice and in retinal explant sections under various conditions. Protein expression of components of the JNK, PI3-K and MAPK transduction cascades were examined by western blot. Inhibitor studies using SP600125, LY294002 and UO126 were carried out in retinal explant cultures.
We report that increased phosphatidylinositol (PI) activity during development results in decreased levels of BimEL transcript, most likely through inhibiting the transcriptional activity of members of the forkhead family. Additionally, we show that as the retina matures activation of the ERK1/2 pathway is necessary to promote BimEL phosphorylation, an event that leads to an increase in the turnover of BimEL protein. Finally, in relation to retinal degeneration we demonstrate that cell death in explants is accompanied by the activation of c-jun N-terminal kinase (JNK) and increased phosphorylation/activation of the transcription factor c-jun. Moreover, treatment of explants with the selective JNK inhibitor SP600125 prevented these events and afforded significant protection against cell death.
These results show that the activation of multiple signaling pathways is required to silence Bim once developmental apoptosis is complete. Our findings also indicate that Bim acts as a sensor to many apoptotic stimuli and is re-expressed under conditions of stress. This induction of Bim is essential for apoptosis and requires JNK activation indicating a critical role for the JNK signaling pathway in mediating retinal apoptosis.
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