The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Amadio, Marialaura; Bucolo, Claudio; Leggio, Gm; Drago, Filippo; Govoni, Stefano; Pascale, Alessia

doi:10.1016/j.bcp.2010.06.033

Cited by 100 publications

(84 citation statements)

References 65 publications

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“…22 The same cascade was investigated in the retina of diabetic rats. 21 However, CoCl 2 did not trigger detectable changes in HuR phosphorylation in our system (not shown).…”

Section: Discussionmentioning

confidence: 58%

“…12,13 With respect to diabetic retinopathy, the levels of both HuR and VEGFA have been shown to be altered in both in vitro and in vivo models. 16,21,22 Given that controlling VEGFA production during hypoxia is important for maintaining tissue function, we set out to examine in detail the effect of a hypoxic mimetic, cobalt chloride (CoCl 2 ), on VEGFA expression. CoCl 2 is widely used as a chemical inducer of the hypoxic response, 23,24 through the CoCl 2 -mediated induced expression of the transcription factor HIF-1a, 17 which governs the transcriptional induction of many oxygendependent genes.…”

Section: Introductionmentioning

confidence: 99%

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Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

et al. 2015

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These authors equally contributed to the work.Keywords: biotin pulldown, mass spectrometry, post-transcriptional gene regulation, polysome profiling, ribonucleoprotein complex, RNA-binding proteins Vascular endothelial growth factor (VEGF) A is a master regulator of neovascularization and angiogenesis. VEGFA is potently induced by hypoxia and by pathological conditions including diabetic retinopathy and tumorigenesis. Finetuning of VEGFA expression by different stimuli is important for maintaining tissue vascularization and organ homeostasis. Here, we tested the effect of the hypoxia mimetic cobalt chloride (CoCl 2 ) on VEGFA expression in human cervical carcinoma HeLa cells. We found that CoCl 2 increased the levels of VEGFA mRNA and VEGFA protein without affecting VEGFA mRNA stability. Biotin pulldown analysis to capture the RNA-binding proteins (RBPs) bound to VEGFA mRNA followed by mass spectrometry analysis revealed that the RBP HuR [human antigen R, a member of the embryonic lethal abnormal vision (ELAV) family of proteins], interacts with VEGFA mRNA. VEGFA mRNA-tagging experiments showed that exposure to CoCl 2 increases the interaction of HuR with VEGFA mRNA and promoted the colocalization of HuR and the distal part of the VEGFA 3 0 -untranslated region (UTR) in the cytoplasm. We propose that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation.

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“…22 The same cascade was investigated in the retina of diabetic rats. 21 However, CoCl 2 did not trigger detectable changes in HuR phosphorylation in our system (not shown).…”

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

et al. 2015

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“…5A). The association of HuR with its target transcripts is modulated by Chk2-(4, 38), protein kinase C (PKC)- (42)(43)(44), and p38…”

Section: Fig 2 Association Of Hur With Tra2␤4 Mrna (A)mentioning

confidence: 99%

HuR Regulates Alternative Splicing of the TRA2β Gene in Human Colon Cancer Cells under Oxidative Stress

Akaike

Masuda

Kuwano

et al. 2014

Molecular and Cellular Biology

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bHu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs. The human TRA2␤ gene encodes splicing factor transformer 2␤ (Tra2␤) and generates 5 mRNA isoforms (TRA2␤1 to -5) through alternative splicing. Exposure of HCT116 colon cancer cells to sodium arsenite stimulated checkpoint kinase 2 (Chk2)-and mitogen-activated protein kinase p38 (p38 MAPK )-mediated phosphorylation of HuR at positions S88 and T118. This induced an association between HuR and the 39-nucleotide (nt) proximal region of TRA2␤ exon 2, generating a TRA2␤4 mRNA that includes exon 2, which has multiple premature stop codons. HuR knockdown or Chk2/p38 MAPK double knockdown inhibited the arsenite-stimulated production of TRA2␤4 and increased Tra2␤ protein, facilitating Tra2␤-dependent inclusion of exons in target pre-mRNAs. The effects of HuR knockdown or Chk2/p38 MAPK double knockdown were also confirmed using a TRA2␤ minigene spanning exons 1 to 4, and the effects disappeared when the 39-nt region was deleted from the minigene. In endogenous HuR knockdown cells, the overexpression of a HuR mutant that could not be phosphorylated (with changes of serine to alanine at position 88 [S88A], S100A, and T118A) blocked the associated TRA2␤4 interaction and TRA2␤4 generation, while the overexpression of a phosphomimetic HuR (with mutations S88D, S100D, and T118D) restored the TRA2␤4-related activities. Our findings revealed the potential role of nuclear HuR in the regulation of alternative splicing programs under oxidative stress. The Hu/embryonic lethal abnormal vision (ELAV) protein family comprises 3 primarily neuronal proteins (HuB, HuC, and HuD) and one ubiquitously expressed protein, HuR (Hu antigen R; also known as HuA). Hu family proteins contain 3 RNA recognition motifs (RRMs) that mediate the specific interaction of Hu proteins with RNA (1). RRMs specifically bind to short, singlestranded stretches of uridines separated by adenosines or, less commonly, other bases (1, 2), which are also known as RNA recognition elements (RREs) or AU-rich elements (AREs), in the 3= untranslated region (UTR) of target mRNAs. HuR plays a crucial role in the regulation of gene expression in cells exposed to mitogenic, differentiation, immune, and stress-inducing agents (1, 3) through stabilizing and/or facilitating the translation of ARE-containing mRNAs for various proteins, including tumor suppressors (p53 and von Hippel-Lindau tumor suppressor), cyclins (A, B1, and D1), proto-oncogene products (c-Fos and c-Myc), growth factors (vascular endothelial growth factor), cytokines (transforming growth factor ␤ and tumor necrosis factor alpha), cyclindependent kinase (Cdk) inhibitors (p21 and p27), antiapoptotic factors (prothymosin ␣ [ProT␣], B-cell CLL/lymphoma 2 [Bcl-2], and myeloid cell leukemia sequence 1 [Mcl-1]), and signaling molecules, such as mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) (4-15). Recently, several key aspects of HuR signaling have emerged; for example, the set of RNAs (...

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“…All the aforementioned observations may lead to the formation of a fourth hypothesis of the initiation of DR, the "glial cells-first" scenario. In this case, Müller cells, by sensing the elevated glucose level, activate their volume and ion-regulating machinery and release vasoproliferative vascular endothelial growth factor (VEGF; Amandio et al, 2010;Eichler et al, 2000) and inflammatory substances (prostaglandins, tumor necrosis factor (TNF), and interleukins; Behl et al, 2008;Joussen et al, 2009;Tang and Kern, 2011). These would in turn initiate neurodegeneration, inflammation, and vascular growth.…”

Section: P0505mentioning

confidence: 99%

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

Szabadfi

Pintér

Reglődi

et al. 2014

International Review of Cell and Molecular Biology

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The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Cited by 100 publications

References 65 publications

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

HuR Regulates Alternative Splicing of the TRA2β Gene in Human Colon Cancer Cells under Oxidative Stress

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

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The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Cited by 100 publications

References 65 publications

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

HuR Regulates Alternative Splicing of the TRA2β Gene in Human Colon Cancer Cells under Oxidative Stress

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

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Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR