Proceedings of the National Academy of Sciences · 2012 · 102 citations · 19 references
Health ProfessionsMolecular BiologyOphthalmologyCell SignalingOcular DiseaseSignal TransductionAge-related Macular DegenerationMacular DegenerationMacular DiseaseMacular DisordersRetinal DegenerationRetinal Pigment EpitheliumErk SignalingExtracellular Signal-regulated Kinase PathwayExtracellular Signal-regulated Kinase SignalingMap KinasesMek InhibitionRetinal Pigment Epithelium DegenerationRetinal Signaling PathwaysRpe Atrophy
Deficient expression of the RNase III DICER1, which leads to the accumulation of cytotoxic Alu RNA, has been implicated in degeneration of the retinal pigmented epithelium (RPE) in geographic atrophy (GA), a late stage of age-related macular degeneration that causes blindness in millions of people worldwide. Here we show increased extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation in the RPE of human eyes with GA and that RPE degeneration in mouse eyes and in human cell culture induced by DICER1 depletion or Alu RNA exposure is mediated via ERK1/2 signaling. Alu RNA overexpression or DICER1 knockdown increases ERK1/2 phosphorylation in the RPE in mice and in human cell culture. Alu RNA-induced RPE degeneration in mice is rescued by intravitreous administration of PD98059, an inhibitor of the ERK1/2-activating kinase MEK1, but not by inhibitors of other MAP kinases such as p38 or JNK. These findings reveal a previously unrecognized function of ERK1/2 in the pathogenesis of GA and provide a mechanistic basis for evaluation of ERK1/2 inhibition in treatment of this disease.
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Initial sequencing and analysis of the human genome
Eric S. Lander, Lauren Linton, Bruce W. Birren et al. · Nature · 2001 · 24.6K citations · Full text
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration
Hiroki Kaneko, Sami Dridi, Valeria Tarallo et al. · Nature · 2011 · 614 citations