TY - JOUR
T1 - 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
AU - Ma, B.
AU - Sen, T.
AU - Asnaghi, L.
AU - Valapala, M.
AU - Yang, F.
AU - Hose, S.
AU - McLeod, D. S.
AU - Lu, Y.
AU - Eberhart, C.
AU - Zigler, J. S.
AU - Sinha, D.
N1 - Funding Information:
Acknowledgements. This work was supported by grants from National Institutes of Health, EY018636 (DS), EY019037 (DS), EY019037-S (DS) and EY01765 (Wilmer Imaging Core); the Helena Rubinstein Foundation (DS) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). We thank the staff members at Spring Valley Laboratories (Woodbine, MD, USA) for taking care of the experimental animals. We also thank Bhaja K Padhi, Eric Wawrousek, Gerard A Lutty, James P Handa, Stanislav Tomarev, Morton F Goldberg and Nilkantha Sen for critically reading and discussions regarding the manuscript.
PY - 2011/10
Y1 - 2011/10
N2 - 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 signalregulated kinase pathways. We propose that βA3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes.
AB - 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 signalregulated kinase pathways. We propose that βA3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes.
KW - Anoikis
KW - Astrocytes
KW - Lens denucleation
KW - PI3K/AKT/mTOR and ERK pathways
KW - βA3/A1-crystallin
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U2 - 10.1038/cddis.2011.100
DO - 10.1038/cddis.2011.100
M3 - Article
C2 - 21993393
AN - SCOPUS:80055015834
SN - 2041-4889
VL - 2
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - e217
ER -