AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-δ: implications for vascular disease

Cai, Weiping; Torreggiani, Massimo; Zhu, Li; Xue, Chunyu; He, John Cijiang; Striker, Gary E.; Vlassara, Helen

doi:10.1152/ajpcell.00463.2009

Cited by 73 publications

(56 citation statements)

References 75 publications

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“…Previously, PKCd has been reported to be implicated in the activation of NADPH oxidase in many cell lines. [35][36][37] However, the molecular mechanisms by which PKCd activates NADPH oxidase have not been elucidated. In this study, we report that PKCd directly binds to p47 phox and phosphorylates Ser348, -379, promoting its translocation to the membrane fraction and activation of NOX1.…”

Section: Discussionmentioning

confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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Section: Discussionmentioning

confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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“…AGE-R1 expression can be upregulated by its ligands but is repressed by prolonged exposure to pro-oxidant stress. Thus increased AGE-R1 expression was seen with a diet low in AGE which also was found to extend life in mice, while increased oxidant stress in diabetes or high AGE diet led eventually to downregulation of AGE-R1 (239,1661). AGE-R3 (also known as galectin-3) may serve as both an AGE clearance receptor and a mediator of macrophage endocytosis of modified LDL (1266).…”

Section: Rage Is Activated By Hyperlipidemiamentioning

confidence: 94%

“…Both promote endocytosis and removal of AGE. Additionally, an important anti-inflammatory mechanism for AGE-R1 appears to be binding of EGFR and inhibition of EGFR transactivation in response to AGE exposure (238,239). AGE exposure results in a marked increase in tyrosine phosphorylation status of the cytoplasmic tail of EGFR, possibly by generation of active Src and/or ROS and resultant inhibition of phosphatases.…”

Section: Rage Is Activated By Hyperlipidemiamentioning

confidence: 99%

“…Activated PKC␦ phosphorylates the p47 phox component of NOX, promoting its translocation to the membrane, NOX activation, and further increased ROS production. AGE receptor 1 (AGE-R1) forms a complex with EGFR, binds AGE, and buffers or inhibits the activation of EGFR (239). PKC␦ would also be expected to activate PYK2 with its numerous proinflammatory effects.…”

Section: Rage Is Activated By Hyperlipidemiamentioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…The biological properties of AGEs have been associated with their ability to interact with several membrane receptors including the receptor for advanced glycation end products (RAGE), the type A macrophage scavenger receptor (20), galectin-3 (21), scavenger receptors class B type 1 (22,23), AGE receptor 1 (24)(25)(26), and polypeptides potentially present on the cell surface (AGE-receptor complex) (21). The best-characterized receptor for AGEs, RAGE, is expressed on many cells that are targeted by HIV-1, such as monocytes and macrophages (27,28), CD4 T cells, and dendritic cells (DCs) (29)(30)(31).…”

mentioning

confidence: 99%

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Nasreddine

Borde

Gozlan

et al. 2011

The Journal of Immunology

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Highly active antiretroviral therapy is associated with carbohydrate metabolic alterations that may lead to diabetes. One consequence of hyperglycemia is the formation of advanced glycation end products (AGEs) that are involved in diabetes complications. We investigated the impact of AGEs on the infection of monocyte-derived dendritic cells (MDDCs) by HIV-1 and the ability of MDDCs to transmit the virus to T cells. We showed that AGEs could inhibit infection of MDDCs with primary R5-tropic HIV-1Ba-L by up to 85 ± 9.2% and with primary X4-tropic HIV-1VN44 by up to 60 ± 8.5%. This inhibitory effect of AGEs was not prevented by a neutralizing anti-receptor for advanced glycation end products (anti-RAGE) Ab, demonstrating a RAGE-independent mechanism. Moreover, AGEs inhibited by 70–80% the transmission in trans of the virus to CD4 T cells. Despite the inhibitory effect of AGEs on both MDDC infection and virus transmission in trans, no inhibition of virus attachment to cell membrane was observed, confirming that attachment and transmission of the virus involve independent mechanisms. The inhibitory effect of AGEs on infection was associated with a RAGE-independent downregulation of CD4 at the cell membrane and by a RAGE-dependent repression of the CXCR4 and CCR5 HIV-1 receptors. AGEs induce the secretion of proinflammatory cytokines IL-6, TNF-α, and IL-12, but not RANTES or MIP-1α, and did not lead to MDDC maturation as demonstrated by the lack of expression of the CD83 molecule. Taken together, our results suggest that AGEs can play an inhibiting role in HIV-1 infection in patients who accumulate circulating AGEs, including patients treated with protease inhibitors that developed diabetes.

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AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-δ: implications for vascular disease

Cited by 73 publications

References 75 publications

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Molecular Biology of Atherosclerosis

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

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