MAP Kinase Pathway is Involved in IGF-1-Stimulated Proliferation of Human Retinal Pigment Epithelial Cells (hRPE)

Weng, Christina Y.; Kothary, Piyush C.; Verkade, Angela J.; Reed, David; Monte, Monte A. Del

doi:10.3109/02713680903177890

Cited by 25 publications

(14 citation statements)

References 27 publications

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“…VEGF activates MAPKs via insulin-like growth factor 1 (IGF1) and recent work on primary human RPE (hRPE) cells has demonstrated that constituents of MAPK pathways are likely to influence IGF1-mediated retinal angiogenesis. [15] We observed AAMD associations with a number of SNPs in insulin signaling system genes. Most notable was a missense variant in insulin-like growth factor-binding protein 1 ( IGFBP1 , Ile253Met, rs4619, P ≤0.003) that yields an amino acid substitution proximal to a cell attachment site in the mature protein (NCBI Reference Sequence: NP_000587.1).…”

Section: Resultsmentioning

confidence: 75%

“…PD98059, a selective inhibitor of MAPK kinases ERK1 and ERK2, suppressed IGF1-induced hRPE cell proliferation and inhibited IGF1-induced VEGF synthesis. [15] Anathrax lethal toxin (LeTx) has a similar activity profile to PD98059 in cancer cell lines [37] and is known to inactivate MAPK signaling pathways by cleaving the amino termini of MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, and MAP2K7 (reviewed in ref [16]). Bromberg-White et al .…”

Section: Discussionmentioning

confidence: 99%

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AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis

SanGiovanni

Lee

2013

PLoS ONE

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PurposeTo determine whether common DNA sequence variants within groups of genes encoding elements of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways are, in aggregate, associated with advanced AMD (AAMD).MethodsWe used meta-regression and exact testing methods to identify AAMD-associated SNPs in 1177 people with AAMD and 1024 AMD-free elderly peers from 3 large-scale genotyping projects on the molecular genetics of AMD. SNPs spanning independent AAMD-associated genomic intervals were examined with a multi-locus-testing method (INRICH) for enrichment within five sets of genes encoding constituents of stress-activated MAPK signaling cascades.ResultsFour-of-five pathway gene sets showed enrichment with AAMD-associated SNPs; findings persisted after adjustment for multiple testing in two. Strongest enrichment signals (P = 0.006) existed in a c-Jun N-terminal kinase (JNK)/MAPK cascade (Science Signaling, STKE CMP_10827). In this pathway, seven independent AAMD-associated regions were resident in 6 of 25 genes examined. These included sequence variants in: 1) three MAP kinase kinase kinases (MAP3K4, MAP3K5, MAP3K9) that phosphorylate and activate the MAP kinase kinases MAP2K4 and MAP2K7 (molecules that phosphorylate threonine and tyrosine residues within the activation loop of JNK); 2) a target of MAP2K7 (JNK3A1) that activates complexes involved in transcriptional regulation of stress related genes influencing cell proliferation, apoptosis, motility, metabolism and DNA repair; and 3) NR2C2, a transcription factor activated by JNK1A1 (a drugable molecule influencing retinal cell viability in model systems). We also observed AAMD-related sequence variants resident in genes encoding PPP3CA (a drugable molecule that inactivates MAP3K5), and two genes (TGFB2, TGFBR2) encoding factors involved in MAPK sensing of growth factors/cytokines.ConclusionsLinkage disequilibrium (LD)-independent genomic enrichment analysis yielded associations of AAMD with aggregates of functionally related genes encoding constituents of the JNK MAPK signaling pathway. FDA-approved drugs now exist to target constituents of stress-activated MAPK pathways and may offer reasonable approaches to preventing or treating AAMD.

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis

SanGiovanni

Lee

2013

PLoS ONE

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“…3), 54,55 such as angiogenesis in diabetic retinopathy (DR) and AMD. 56,57 Through different signal transduction mediators, ligand activation of IGF1R by IGF-1 may also lead to the ubiquitin-mediated degradation of IGF1R (3 in Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Associations between Genetic Polymorphisms of Insulin-like Growth Factor Axis Genes and Risk for Age-Related Macular Degeneration

Chiu

Conley

Gorin

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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“…The retinal pigment epithelium (RPE), a polarized monolayer of specialized epithelium and a glial cell layer located between the neural retina and choroid, plays a pivotal role in supporting photoreceptor function [1, 2]. RPE cells function as the guardians and caretakers of the photoreceptors.…”

Section: Introductionmentioning

confidence: 99%

Blockage of Notch Signaling Inhibits the Migration and Proliferation of Retinal Pigment Epithelial Cells

Liu

Jin

Long

et al. 2013

The Scientific World Journal

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The Notch signaling is an evolutionarily conserved cell-cell communication pathway that plays critical roles in the proliferation, survival, apoptosis, and fate determination of mammalian cells. Retinal pigment epithelial (RPE) cells are responsible for supporting the function of the neural retina and maintaining vision. This study investigated the function of Notch signaling in RPE cells. We found that the members of the Notch signaling pathway components were differentially expressed in RPE cells. Furthermore, blockage of Notch signaling inhibited the migration and proliferation of RPE cells and reduced the expression levels of certain Notch signaling target genes, including HES1, MYC, HEY2, and SOX9. Our data reveal a critical role of Notch signaling in RPE cells, suggesting that targeting Notch signaling may provide a novel approach for the treatment of ophthalmic diseases related to RPE cells.

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MAP Kinase Pathway is Involved in IGF-1-Stimulated Proliferation of Human Retinal Pigment Epithelial Cells (hRPE)

Abstract: These studies suggest that IGF-1 is a mitogen for hRPE cells and also stimulates production of the angiogenic factor, VEGF. Additionally, PD98059 inhibits the production of VEGF, suggesting that the MAP kinase pathway is involved in IGF-1-mediated angiogenesis.

Cited by 25 publications

References 27 publications

AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis

AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis

Associations between Genetic Polymorphisms of Insulin-like Growth Factor Axis Genes and Risk for Age-Related Macular Degeneration

Blockage of Notch Signaling Inhibits the Migration and Proliferation of Retinal Pigment Epithelial Cells

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