September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The tyrosine phosphatase receptor PTPRZ1 inhibits β-catenin-dependent gene expression in RPE cells
Author Affiliations & Notes
  • Jorgelina Muriel Calandria
    Neuroscience Center of Excellence, LSU Health Sciences Center , New Orleans, Louisiana, United States
  • Khanh Do
    Neuroscience Center of Excellence, LSU Health Sciences Center , New Orleans, Louisiana, United States
  • Swornim Shrestha
    Neuroscience Center of Excellence, LSU Health Sciences Center , New Orleans, Louisiana, United States
  • Nicolas G Bazan
    Neuroscience Center of Excellence, LSU Health Sciences Center , New Orleans, Louisiana, United States
  • Footnotes
    Commercial Relationships   Jorgelina Calandria, None; Khanh Do, None; Swornim Shrestha, None; Nicolas Bazan, None
  • Footnotes
    Support  Supported by NIGMS grant P30 GM103340 and NEI grant R01 EY005121 (NGB) and Research to Prevent Blindness
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6051. doi:
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    • Get Citation

      Jorgelina Muriel Calandria, Khanh Do, Swornim Shrestha, Nicolas G Bazan; The tyrosine phosphatase receptor PTPRZ1 inhibits β-catenin-dependent gene expression in RPE cells. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6051.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : PTPRZ1 is a tyrosine phosphatase receptor that stabilizes the cadherin/catenin complex at cell-cell junctions. The retinal pigment epithelium (RPE) relies on these cell-cell interactions to maintain the integrity and polarization of the monolayer in the retina. β-catenin may be released from the complex and translocated into the nucleus. Neuroprotectin D1 (NPD1), a bioactive derivative of docosahexaenoic acid (DHA), modulates gene expression upon stress conditions (Calandria et al, 2015. Cell Death Differ) . We propose that the inhibition of PTPRZ1 by HMGB1 promotes the release of β-catenin from the cell-cell junction complex and, along with NPD1, favors its nuclear translocation to modulate gene expression and promote survival of RPE.

Methods : Primary RPE cells were exposed to 600 µM H2O2 and 10ng/ml TNFα to induce oxidative stress. β-catenin release and translocation was assessed by immunocytochemistry. Gene expression was measured by real-time PCR. Silencing and overexpression of PTPRZ1 and HMGB1 was carried out by transfecting RPE cells with siRNA and vectors carrying the open reading frame. TCF/LEF-β-catenin activity was measured using a TOP Flash system driving the expression of luciferase.

Results : The addition of HMGB1 in the medium induced an increase in the mobilization of β-catenin from the membrane to the cytoplasm. The silencing of PTPRZ1 induced the same effect, suggesting that HMGB1 acts through the inhibition of the tyrosine phosphatase receptor. NPD1 and HMGB1 separately increased the nuclear translocation of β-catenin. Intriguingly, HMGB1, and not NPD1, induced a rise in TCF/LEF activity, suggesting that both effects proceed through different pathways. The wnt/β-catenin canonical genes CCND1, CLDN1 and MMP2 were modulated by HMGB1 but not affected by NPD1. On the other hand, FOXO3a-driven genes BIM, CDKN1A and CDKN1B expression was influenced by HMGB1 and NPD1 in an additive manner.

Conclusions : Altogether, these results suggest that NPD1 and HMGB1 act cooperatively, but through different pathways, to modulate β-catenin activity. Suppression of PTPRZ1 plus addition of NPD1 lead to an increased mobilization and nuclear translocation of β-catenin, affecting its activity in a differently. The modulation of the β-catenin activity may be used as a therapeutic instrument to promote retinal cell remodeling and survival.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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