PMID- 22869729 OWN - NLM STAT- MEDLINE DCOM- 20121031 LR - 20211021 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 109 IP - 34 DP - 2012 Aug 21 TI - ERK1/2 activation is a therapeutic target in age-related macular degeneration. PG - 13781-6 LID - 10.1073/pnas.1206494109 [doi] AB - 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. FAU - Dridi, Sami AU - Dridi S AD - Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40506, USA. FAU - Hirano, Yoshio AU - Hirano Y FAU - Tarallo, Valeria AU - Tarallo V FAU - Kim, Younghee AU - Kim Y FAU - Fowler, Benjamin J AU - Fowler BJ FAU - Ambati, Balamurali K AU - Ambati BK FAU - Bogdanovich, Sasha AU - Bogdanovich S FAU - Chiodo, Vince A AU - Chiodo VA FAU - Hauswirth, William W AU - Hauswirth WW FAU - Kugel, Jennifer F AU - Kugel JF FAU - Goodrich, James A AU - Goodrich JA FAU - Ponicsan, Steven L AU - Ponicsan SL FAU - Hinton, David R AU - Hinton DR FAU - Kleinman, Mark E AU - Kleinman ME FAU - Baffi, Judit Z AU - Baffi JZ FAU - Gelfand, Bradley D AU - Gelfand BD FAU - Ambati, Jayakrishna AU - Ambati J LA - eng GR - RC1EY020442/EY/NEI NIH HHS/United States GR - R01 EY017182/EY/NEI NIH HHS/United States GR - RC1 EY020442/EY/NEI NIH HHS/United States GR - R01 EY020672/EY/NEI NIH HHS/United States GR - P30 EY003040/EY/NEI NIH HHS/United States GR - T32 HL091812/HL/NHLBI NIH HHS/United States GR - T32HL091812/HL/NHLBI NIH HHS/United States GR - UL1 TR001998/TR/NCATS NIH HHS/United States GR - R01 EY022238/EY/NEI NIH HHS/United States GR - UL1 TR000117/TR/NCATS NIH HHS/United States GR - R01EY001545/EY/NEI NIH HHS/United States GR - R01EY020672/EY/NEI NIH HHS/United States GR - R01EY017950/EY/NEI NIH HHS/United States GR - UL1RR033173/RR/NCRR NIH HHS/United States GR - P30EY021721/EY/NEI NIH HHS/United States GR - R01GM068414/GM/NIGMS NIH HHS/United States GR - TL1 RR033172/RR/NCRR NIH HHS/United States GR - R01EY022238/EY/NEI NIH HHS/United States GR - R01 EY018350/EY/NEI NIH HHS/United States GR - R01 GM068414/GM/NIGMS NIH HHS/United States GR - P30EY003040/EY/NEI NIH HHS/United States GR - TL1 TR000115/TR/NCATS NIH HHS/United States GR - UL1 RR033173/RR/NCRR NIH HHS/United States GR - R21EY019778/EY/NEI NIH HHS/United States GR - R21 EY019778/EY/NEI NIH HHS/United States GR - R01EY018350/EY/NEI NIH HHS/United States GR - R01 EY018836/EY/NEI NIH HHS/United States GR - R01 EY001545/EY/NEI NIH HHS/United States GR - K08EY021521/EY/NEI NIH HHS/United States GR - K08EY021757/EY/NEI NIH HHS/United States GR - R01EY017182/EY/NEI NIH HHS/United States GR - K08 EY021757/EY/NEI NIH HHS/United States GR - R01 EY017950/EY/NEI NIH HHS/United States GR - P30 EY021721/EY/NEI NIH HHS/United States GR - P30 EY014800/EY/NEI NIH HHS/United States GR - K08 EY021521/EY/NEI NIH HHS/United States GR - R01EY018836/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120806 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - EC 2.7.11.24 (MAPK1 protein, human) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.26.3 (DICER1 protein, human) RN - EC 3.1.26.3 (Dicer1 protein, mouse) RN - EC 3.1.26.3 (Ribonuclease III) RN - EC 3.6.4.13 (DEAD-box RNA Helicases) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) SB - IM MH - Animals MH - DEAD-box RNA Helicases/metabolism MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Flavonoids/pharmacology MH - *Gene Expression Regulation, Enzymologic MH - Humans MH - Macular Degeneration/*enzymology/*therapy MH - Mice MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3/*metabolism MH - Phosphorylation MH - Retinal Pigment Epithelium/metabolism MH - Ribonuclease III/metabolism MH - Signal Transduction PMC - PMC3427082 COIS- The authors declare no conflict of interest. EDAT- 2012/08/08 06:00 MHDA- 2012/11/01 06:00 PMCR- 2013/02/21 CRDT- 2012/08/08 06:00 PHST- 2012/08/08 06:00 [entrez] PHST- 2012/08/08 06:00 [pubmed] PHST- 2012/11/01 06:00 [medline] PHST- 2013/02/21 00:00 [pmc-release] AID - 1206494109 [pii] AID - 201206494 [pii] AID - 10.1073/pnas.1206494109 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13781-6. doi: 10.1073/pnas.1206494109. Epub 2012 Aug 6.