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PDGF- and insulin/IGF-1-specific distinct modes of class IA PI 3-kinase activation in normal rat retinas and RGC-5 retinal ganglion cells.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Biswas, Swarajit K. Zhao, Yan Nagalingam, Arumugam Gardner, Thomas W. Sandirasegarane, Lakshman |
| Copyright Year | 2008 |
| Abstract | PURPOSE To compare PDGF- and insulin/IGF-1-induced class I(A) PI 3-kinase/Akt survival signaling in normal retinas and retinal ganglion cells (RGCs). METHODS Normal rat retinas and RGC-5 cells were used for (1) immunohistochemical and immunoblot studies to detect PDGF receptor (PDGFR) subtypes and (2) immunoprecipitation, immunoblot, and in vitro lipid kinase assays to determine basal and PDGF-induced class I(A) PI 3-kinase/Akt survival signaling, in comparison with insulin or IGF-1 responses. Furthermore, RGC-5 cells were exposed to broad-spectrum (LY294002) or p110 isoform-selective (PI-103) PI 3-kinase inhibitors (versus Akt inhibitor) to assess the consequent effects on Akt phosphorylation, caspase-3/PARP cleavage, apoptotic phenotype, and cell viability, as a function of serum trophic factors. RESULTS PDGFR-alpha and -beta immunoreactivity was observed in rat retinal Müller cells and in the RGC layer and blood vessels, respectively. In addition, PDGFR-alpha and -beta protein expression was observed in RGC-5 cells. Both retinas and RGC-5 cells exhibited a similar pattern of subunit-specific basal class I(A) PI 3-kinase activity, which was stimulated in a temporal and signal-specific manner by PDGF and insulin/IGF-1. Furthermore, RGC-5 cells showed PDGFR-alpha/beta tyrosine phosphorylation that induced the p85alpha regulatory subunit to activate p110alpha/beta-associated class I(A) PI 3-kinase, which in turn enhanced Akt phosphorylation. Exposure of serum-deprived RGC-5 cells to PI 3-kinase or Akt inhibitors increased susceptibility to apoptotic phenotype as revealed by caspase-3 and PARP cleavage. CONCLUSIONS The present findings provide direct evidence of two distinct modes of retinal class I(A) PI 3-kinase activation that occurs in response to PDGF receptor and insulin/IGF-1 receptor stimulation. PDGF-induced PI 3-kinase/PIP3/Akt axis may provide new therapeutic approaches to ameliorate cell death in diabetic retinopathy and other retinal neurodegenerations. |
| Starting Page | 105 |
| Ending Page | 112 |
| Page Count | 8 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.iovs.org/content/49/8/3687.full.pdf |
| PubMed reference number | 18421086v1 |
| Alternate Webpage(s) | https://doi.org/10.1167/iovs.07-1455 |
| DOI | 10.1167/iovs.07-1455 |
| Journal | Investigative ophthalmology & visual science |
| Volume Number | 49 |
| Issue Number | 8 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Activation action Adrenergic alpha-Agonists Axis vertebra Blood Vessel Cell Death Cell Survival Cessation of life Diabetic Retinopathy Ganglion cell Immunoblotting Insulin-Like-Growth Factor I Receptor LY 294002 Platelet-Derived Growth Factor Receptor Proto-Oncogene Proteins c-akt Retina Retinal Diseases Retinal Ganglion Cells Subtype (attribute) Tyrosine Phosphorylation caspase-3 protein expression |
| Content Type | Text |
| Resource Type | Article |
