Journal
CELL DEATH & DISEASE
Volume 2, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2011.100
Keywords
anoikis; astrocytes; beta A3/A1-crystallin; lens denucleation; PI3K/AKT/mTOR and ERK pathways
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Funding
- National Institutes of Health [EY018636, EY019037, EY019037-S, EY01765]
- Helena Rubinstein Foundation
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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 beta A3/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 beta A3/A1-crystallin has a role in anoikis, we induced anoikis in vitro and conducted mechanistic studies on astrocytes, cells known to express beta A3/A1-crystallin. The expression pattern of Bit1 in retina correlates temporally with the development of astrocytes. Our data also indicate that loss of beta A3/A1-crystallin in astrocytes results in a failure of Bit1 to be trafficked to the Golgi, thereby suppressing anoikis. This loss of beta A3/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 beta A3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes. Cell Death and Disease (2011) 2, e217; doi: 10.1038/cddis.2011.100; published online 13 October 2011
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