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PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy

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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.

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (NSFC:31100991, 81400425), Tianjin Municipal Science and Technology Commission Grants (13JCYBJC23300,11JCYBJC09900), the joint project by Doctoral Fund of Ministry of Education doctoral subject (20111202110009), and Tianjin Medical University Eye Hospital Science Grant of PhD (20120403).

Conflict of interest

The authors have no conflicts of interest of a financial nature or otherwise.

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Authors and Affiliations

  1. Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China

    Lijie Dong, Hong Nian, Yan Shao, Yan Zhang, Yue Yi, Fang Tian, Wenbo Li, Hong Zhang, Xiaomin Zhang, Fei Wang & Xiaorong Li

  2. Tianjin Medical University Eye Institute, Tianjin, People’s Republic of China

    Lijie Dong, Hong Nian, Yan Zhang, Yue Yi, Xiaomin Zhang, Fei Wang & Xiaorong Li

  3. The School of Optometry and Ophthalmology, TMU, No. 251, Fu kang Road,Nan Kai District, Tianjin, 300384, People’s Republic of China

    Lijie Dong, Hong Nian, Yan Shao, Yan Zhang, Yue Yi, Fang Tian, Wenbo Li, Hong Zhang, Xiaomin Zhang, Fei Wang & Xiaorong Li

  4. Jiangsu Berkgen Biopharmaceutical Inc., Ltd, No. 20, Jian Hua Road, Hang Jiang District, Yangzhou, Jiangsu province, 225128, People’s Republic of China

    Fei Wang

  5. Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, USA

    Qiutang Li

Authors
  1. Lijie Dong
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  2. Hong Nian
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  4. Yan Zhang
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  6. Yue Yi
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  7. Fang Tian
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  8. Wenbo Li
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  9. Hong Zhang
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  10. Xiaomin Zhang
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  11. Fei Wang
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  12. Xiaorong Li
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Corresponding authors

Correspondence to Lijie Dong, Fei Wang or Xiaorong Li.

Additional information

Lijie Dong, Hong Nian and Yan Shao contributed equally to this paper

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Dong, L., Nian, H., Shao, Y. et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy. Cell Tissue Res 360, 233–243 (2015). https://doi.org/10.1007/s00441-014-2104-5

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  • DOI: https://doi.org/10.1007/s00441-014-2104-5

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