βA3/A1-Crystallin controls anoikis-mediated cell death in astrocytes by modulating PI3K/AKT/mTOR and ERK survival pathways through the PKD/Bit1-signaling axis
Open Access
- 13 October 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 2 (10), e217
- https://doi.org/10.1038/cddis.2011.100
Abstract
During eye development, apoptosis is vital to the maturation of highly specialized structures such as the lens and retina. Several forms of apoptosis have been described, including anoikis, a form of apoptosis triggered by inadequate or inappropriate cell–matrix contacts. The anoikis regulators, Bit1 (Bcl-2 inhibitor of transcription-1) and protein kinase-D (PKD), are expressed in developing lens when the organelles are present in lens fibers, but are downregulated as active denucleation is initiated. We have previously shown that in rats with a spontaneous mutation in the Cryba1 gene, coding for βA3/A1-crystallin, normal denucleation of lens fibers is inhibited. In rats with this mutation (Nuc1), both Bit1 and PKD remain abnormally high in lens fiber cells. To determine whether βA3/A1-crystallin has a role in anoikis, we induced anoikis in vitro and conducted mechanistic studies on astrocytes, cells known to express βA3/A1-crystallin. The expression pattern of Bit1 in retina correlates temporally with the development of astrocytes. Our data also indicate that loss of βA3/A1-crystallin in astrocytes results in a failure of Bit1 to be trafficked to the Golgi, thereby suppressing anoikis. This loss of βA3/A1-crystallin also induces insulin-like growth factor-II, which increases cell survival and growth by modulating the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR and extracellular signal-regulated kinase pathways. We propose that βA3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes.Keywords
This publication has 40 references indexed in Scilit:
- A developmental defect in astrocytes inhibits programmed regression of the hyaloid vasculature in the mammalian eyeEuropean Journal of Cell Biology, 2011
- Lens fibre cell differentiation and organelle loss: many paths lead to clarityPhilosophical Transactions Of The Royal Society B-Biological Sciences, 2011
- Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the ratJournal of Cell Science, 2011
- Protein Kinase D Is a Positive Regulator of Bit1 Apoptotic FunctionPublished by Elsevier BV ,2008
- Anoikis effector Bit1 negatively regulates Erk activityProceedings of the National Academy of Sciences of the United States of America, 2008
- βA3/A1-crystallin in astroglial cells regulates retinal vascular remodeling during developmentMolecular and Cellular Neuroscience, 2008
- Precursor Igf-ii (Proigf-ii) And Mature Igf-ii (Migf-ii) Induce Bcl-2 And Bcl-xlExpression Through Different Signaling Pathways In Breast Cancer CellsGrowth Factors, 2008
- A potential role for β- and γ-crystallins in the vascular remodeling of the eyeDevelopmental Dynamics, 2005
- Cell DeathCell, 2004
- Anoikis mechanismsCurrent Opinion in Cell Biology, 2001