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B. Liu, G. Suyeoka, N. Du, A. H. Neufeld; TGFβ/Gadd45b Pathway in the RPE: An Intrinsic Growth Arresting Mechanism That Prohibits RPE Cells From Proliferation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6225.
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© ARVO (1962-2015); The Authors (2016-present)
Regeneration of retinal pigment epithelium (RPE) is critical for regaining retina integrity in the treatment of age related macular degeneration. However, RPE cells behave as stable cells in vivo and cannot proliferate effectively, especially when Bruch’s membrane is damaged. We have studied an intrinsic growth arresting mechanism that prohibits RPE cells from proliferation. Growth arrest and DNA damage inducible protein 45b (Gadd45b) is a cell cycle regulator that arrests cells at G2/M phase. We have correlated Gadd45b expression with growth arrest of the RPE cells.
The expression of Gadd45b and its upstream regulator TGFβ receptors were detected by quantitative RT-PCR, immunohistochemistry or immunoblot in RPE in vivo and in vitro. ARPE-19, a human primary RPE cell line, was used to study the correlation between Gadd45b expression and cell growth arrest in vitro.
As detected by both quantitative RT-PCR and immunohistochemistry, Gadd45b is present in RPE in vivo. In vitro, ARPE-19 cells proliferate in cell cultures but undergo significant growth arrest when cells reach 100% confluence as a monolayer. As detected by quantitative RT-PCR and immunoblot, the expression level of Gadd45b is low in proliferating ARPE-19 but is significantly upregulated when the cells reach confluence under growth arrest. After a wound is made on the confluent monolayer cells, ARPE-19 cannot downregulate the expression level of Gadd45b to release itself into cell cycling efficaciously. Gadd45b is induced by TGFβ signaling, which is present in ARPE-19 in vitro and RPE in vivo. TGFβ receptor I and receptor II expression are significantly upregulated in parallel with Gadd45b expression.
Our results are consistent with the upregulation of Gadd45b, in an autocrine manner, to produce growth arrest in the RPE. TGFβ/Gadd45b may be an intrinsic regulatory mechanism prohibiting RPE from proliferation. Further studies on regulation of the TGFβ/Gadd45b pathway may provide approaches to facilitate RPE regeneration.
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