Calcium-independent Phospholipase A2γ Enhances Activation of the ATF6 Transcription Factor during Endoplasmic Reticulum Stress

Elimam, Hanan; Papillon, Joan; Takano, Tomoko; Cybulsky, Andrey V.

doi:10.1074/jbc.m114.592261

Cited by 16 publications

(36 citation statements)

References 42 publications

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“…Stimulation of iPLA 2 ␥ was dependent on phosphorylation of Ser-511 and/or Ser-515 via MNK1 (MAPK-interacting kinase 1) (20). In addition to characterizing these signaling pathways, we showed that overexpression of iPLA 2 ␥ in cultured GECs reduced complement-mediated GEC injury (19) as well as injury by tunicamycin, which was associated with augmentation of the ATF6 (activating transcription factor 6) pathway of the unfolded protein response in the ER (21). In other cells, such as primary cultures of rabbit renal proximal tubules cells, knockdown of iPLA 2 ␥ expression increased lipid peroxidation and impaired mitochondrial function (22).…”

mentioning

confidence: 91%

“…The detailed method and characterization of the cells was published previously (21). Briefly, by quantitative reverse polymerase chain reaction, iPLA 2 ␥ mRNA was present in cells derived from WT mice but was completely absent in cells from KO mice.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, by quantitative reverse polymerase chain reaction, iPLA 2 ␥ mRNA was present in cells derived from WT mice but was completely absent in cells from KO mice. WT and KO cell lines expressed the podocyte proteins, synaptopodin and nephrin (12,14,21). The cells were cultured on plastic substratum in K1 medium and were used at passages 2-20.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study (21), we demonstrated that in cultured GECs, iPLA 2 ␥, via its localization at the ER, amplified the activation of the ATF6 pathway of the unfolded protein response. Amplification of ATF6 resulted in the up-regulation of the ER chaperones, GRP78 (BiP) and GRP94 (21).…”

Section: Ipla 2 ␥ Deletion Does Not Affect Baseline Urinary Albuminmentioning

confidence: 99%

“…Amplification of ATF6 resulted in the up-regulation of the ER chaperones, GRP78 (BiP) and GRP94 (21). Conversely, deletion of iPLA 2 ␥ blunted these responses, as shown in cultured GECs derived from WT and iPLA 2 ␥ KO mice (21). Therefore, we undertook to examine the expression of ER chaperones in podocytes in vivo by immunoblotting.…”

Section: Ipla 2 ␥ Deletion Does Not Affect Baseline Urinary Albuminmentioning

confidence: 99%

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Genetic Ablation of Calcium-independent Phospholipase A2γ Induces Glomerular Injury in Mice

Elimam

Papillon

Kaufman

et al. 2016

Journal of Biological Chemistry

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Glomerular visceral epithelial cells (podocytes) play a critical role in the maintenance of glomerular permselectivity. Podocyte injury, manifesting as proteinuria, is the cause of many glomerular diseases. We reported previously that calcium-independent phospholipase A 2 ␥ (iPLA 2 ␥) is cytoprotective against complement-mediated glomerular epithelial cell injury. Studies in iPLA 2 ␥ KO mice have demonstrated an important role for iPLA 2 ␥ in mitochondrial lipid turnover, membrane structure, and metabolism. The aim of the present study was to employ iPLA 2 ␥ KO mice to better understand the role of iPLA 2 ␥ in normal glomerular and podocyte function as well as in glomerular injury. We show that deletion of iPLA 2 ␥ did not cause detectable albuminuria; however, it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice. Moreover, after induction of anti-glomerular basement membrane nephritis in young mice, iPLA 2 ␥ KO mice exhibited significantly increased levels of albuminuria, podocyte injury, and loss of podocytes compared with wild type. Thus, iPLA 2 ␥ has a protective functional role in the normal glomerulus and in glomerulonephritis. Understanding the role of iPLA 2 ␥ in glomerular pathophysiology provides opportunities for the development of novel therapeutic approaches to glomerular injury and proteinuria.

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mentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Ipla 2 ␥ Deletion Does Not Affect Baseline Urinary Albuminmentioning

confidence: 99%

Section: Ipla 2 ␥ Deletion Does Not Affect Baseline Urinary Albuminmentioning

confidence: 99%

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Genetic Ablation of Calcium-independent Phospholipase A2γ Induces Glomerular Injury in Mice

Elimam

Papillon

Kaufman

et al. 2016

Journal of Biological Chemistry

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Preclinical activity of fluvastatin‐loaded self‐nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis

Elimam

Hussein

Abdel-Latif

et al. 2022

J of Cellular Biochemistry

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Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EACbearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3.Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.

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Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases

Hara

Yoda

Sasaki

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Calcium-independent Phospholipase A2γ Enhances Activation of the ATF6 Transcription Factor during Endoplasmic Reticulum Stress

Cited by 16 publications

References 42 publications

Genetic Ablation of Calcium-independent Phospholipase A2γ Induces Glomerular Injury in Mice

Genetic Ablation of Calcium-independent Phospholipase A2γ Induces Glomerular Injury in Mice

Preclinical activity of fluvastatin‐loaded self‐nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis

Calcium-independent phospholipase A2γ (iPLA2γ) and its roles in cellular functions and diseases

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