title: 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.
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.
authors: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: B
authors: B
authors: Ma
authors: T
authors: T
authors: Sen
authors: L
authors: L
authors: Asnaghi
authors: M
authors: M
authors: Valapala
authors: F
authors: F
authors: Yang
authors: S
authors: S
authors: Hose
authors: D S
authors: DS
authors: McLeod
authors: Y
authors: Y
authors: Lu
authors: C
authors: C
authors: Eberhart
authors: J S
authors: JS
authors: Zigler
authors: D
authors: D
authors: Sinha
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003459:Crystallins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D003459:Crystallins; C526189:betaA3-crystallin, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002265:Carboxylic Ester Hydrolases