PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation.

Abstract:

:Retinal pigment epithelial (RPE) cells increase in size and multinucleate during aging. We have shown using human and mouse cell lines that oxidised photoreceptor outer segments (oxPOS)-induced cytokinesis failure is related to RPE cell multinucleation, although the underlying mechanism remains unknown. This study investigated the role of the PKC pathway in oxPOS-induced RPE multinucleation using ARPE19 cells. oxPOS treatment promoted PKC activity and upregulated the mRNA expression of PKC α, δ, ζ, ι and μ. Inhibition of PKCα with Gӧ6976 resulted in a 33% reduction of multinucleate ARPE19 cells, whereas inhibition of PKCζ with Gӧ6983 led to a 50% reduction in multinucleate ARPE19 cells. Furthermore, oxPOS treatment induced a PKCζ-dependent upregulation of the Cdk inhibitor p27kip1, its inhibition using A2CE reduced oxPOS-induced ARPE19 multinucleation. Our results suggest that oxPOS-induced ARPE19 cytokinesis failure is, at least in part, due to the upregulation of p27kip1 through activating the PKC, particularly PKCζ pathway. Targeting the PKCζ-p27kip1 signalling axis may be a novel approach to restore RPE repair capacity during aging.

journal_name

Aging (Albany NY)

journal_title

Aging

authors

Rajapakse D,Chen M,Curtis TM,Xu H

doi

10.18632/aging.101299

subject

Has Abstract

pub_date

2017-10-09 00:00:00

pages

2052-2068

issue

10

issn

1945-4589

pii

101299

journal_volume

9

pub_type

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