title: PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy.
abstract: Pathological retinal neovascularization, including retinopathy of prematurity and age-related macular degeneration, is the most common cause of blindness worldwide. Insulin-like growth factor-1 (IGF-1) has a direct mitogenic effect on endothelial cells, which is the basis of angiogenesis. Vascular endothelial growth factor (VEGF) activation in response to IGF-1 is well documented; however, the molecular mechanisms responsible for the termination of IGF-1 signaling are still not completely elucidated. Here, we show that the polypyrimidine tract-binding protein-associated splicing factor (PSF) is a potential negative regulator of VEGF expression induced by IGF stimulation. Functional analysis demonstrated that ectopic expression of PSF inhibits IGF-1-stimulated transcriptional activation and mRNA expression of the VEGF gene, whereas knockdown of PSF increased IGF-1-stimulated responses. PSF recruited Hakai to the VEGF transcription complex, resulting in inhibition of IGF-1-mediated transcription. Transfection with Hakai siRNA reversed the PSF-mediated transcriptional repression of VEGF gene transcription. In summary, these results show that PSF can repress the transcriptional activation of VEGF stimulated by IGF-1 via recruitment of the Hakai complex and delineate a novel regulatory mechanism of IGF-1/VEGF signaling that may have implications in the pathogenesis of neovascularization in ocular diseases.
authors: Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China, aitaomubang@126.com.
authors: Lijie
authors: L
authors: Dong
authors: Hong
authors: H
authors: Nian
authors: Yan
authors: Y
authors: Shao
authors: Yan
authors: Y
authors: Zhang
authors: Qiutang
authors: Q
authors: Li
authors: Yue
authors: Y
authors: Yi
authors: Fang
authors: F
authors: Tian
authors: Wenbo
authors: W
authors: Li
authors: Hong
authors: H
authors: Zhang
authors: Xiaomin
authors: X
authors: Zhang
authors: Fei
authors: F
authors: Wang
authors: Xiaorong
authors: X
authors: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D010100:Oxygen / Q000009:adverse effects* / Q000494:pharmacology; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; C519530:insulin-like growth factor-1, mouse; C467480:vascular endothelial growth factor A, mouse; D007334:Insulin-Like Growth Factor I; D010100:Oxygen