Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 42, Pages 15408-15417Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.010130
Keywords
phosphatidylinositide 3-kinase (PI 3-kinase); Akt PKB; mouse double minute 2 homolog (MDM2); p53; migration
Categories
Funding
- National Institutes of Health [R01EY012509]
- Research to Prevent Blindness
- China Scholarship Council [01806320148]
- Department of Ophthalmology, Harvard Medical School
Ask authors/readers for more resources
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cell-surface molecules to intracellular protein effectors. Key PI3Ks include PI3K?, PI3K?, and PI3K?, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. However, which PI3K isoforms are involved in PVR is unknown. A major characteristic of PVR is the formation of epi (or sub)-retinal membranes that consist of extracellular matrix and cells, including retinal pigment epithelium (RPE) cells, glial cells, and macrophages. RPE cells are considered key players in PVR pathogenesis. Using immunoblotting and immunofluorescence analyses, we herein provide the evidence that PI3K? is highly expressed in human RPEs when it is primarily expressed in leukocytes. We also found that PI3K? inactivation through two approaches, CRISPR/Cas9-mediated depletion and a PI3K?-specific inhibitor (idelalisib), not only blocks vitreous-induced activation of AKT and MDM2 but also abrogates a vitreous-stimulated decrease in p53. Furthermore, we demonstrate that PI3K? inactivation prevents vitreous-induced proliferation, migration, and contraction of human RPEs. These results suggest that PI3K? may represent a potential therapeutic target for RPE-related eye diseases, including PVR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available