Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent

Kinscherf, Ralf; Claus, Ralf A.; Wagner, Martin; Gehrke, Christof; Kamencic, Huse; Hou, Dongming; Nauen, Olaf; Schmiedt, W.; Kovács, Gyula; Pill, Johannes; Metz, J.; Deigner, Hans‐Peter

doi:10.1096/fasebj.12.6.461

Cited by 130 publications

(112 citation statements)

References 46 publications

(47 reference statements)

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“…This change in the redox environment of the mitochondria inhibits pyruvate carboxylase and enhances the toxicity of *NO (Kim et al, 2001). Another mechanism for SOD-2-induced apoptosis is through its ability to activate p53 by the production of H 2 O 2 (Huang et al, 2000;Kinscherf et al, 1998). We have demonstrated that expression of mac25/IGFBP-rP1 is associated with activation of p53; therefore, this mechanism of induction of apoptosis by SOD-2 through p53 is relevant to the current model (Sprenger et al, 2002).…”

Section: Discussionmentioning

confidence: 77%

Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

et al. 2003

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Increased expression of mac25/insulin-like growth factor binding-protein related protein-1 (IGFBP-rP1) in human breast and prostate epithelial cell lines results in the suppression of tumor growth. CDNA expression array analysis revealed increased manganese superoxide dismutase (SOD-2) expression in the mac25/IGFBP-rP1-transfected M12 human prostate cancer cell line compared to M12 control cells. SOD-2 has been postulated to be a tumor suppressor. SOD-2 was also increased in LNCaP cells stably transfected with mac25/IGFBP-rP1, but not in mac25/IGFBP-rP1-transfected PC-3 cells. Mac25 LNCaP cells had a marked decrease in tumor growth in nude mice compared to controls, but there was no difference in tumor growth in mac25 PC-3 cells compared to control. Phosphorylated Erk and Akt were increased in the M12 and LNCaP transfected mac25/ IGFBP-rP1 cells but not PC-3 mac25. Inhibition of PI-3 kinase results in a marked decrease in viability of the M12-mac25 cells compared to M12 controls. Cells treated with H 2 O 2 result in an increase in phospho-ERK. Transfection of SOD-2 in M12 cells markedly decreased tumor growth, apoptosis, G1 delay in the cell cycle, and expression of senescence associated b-galactosidase. These results suggest that one of the downstream mediators of the senescence-associated tumor suppression effect of mac25/IGFBP-rP1 is SOD-2.

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Section: Discussionmentioning

confidence: 77%

Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

et al. 2003

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“…Then the cells were washed and scraped from the plate, extracted, and Western blot performed using anti-PARP monoclonal antibody. The band shown in the ®gure was at 116 kDa, which was degraded into 85 kDa fragment limiting enzyme in the synthesis of GSH, and several reports indicate that treatment of cells with TNF reduces intracellular GSH levels (Ishii et al, 1992;Shoji et al, 1995;Goossens et al, 1995;Phelps et al, 1995;Liu et al, 1998;Kinscherf et al, 1998) and treatments that enhance intracellular GSH levels (Ishii et al, 1992;Goossens et al, 1995;Mehlen et al, 1996;Obrador et al, 1997;Fernandez-Checa et al, 1997;Kinscherf et al, 1998) protect cells from TNFmediated cytotoxicity. Thus one possible mechanism by which g-GCS protects cells from TNF-induced cytotoxicity is through generation of GSH.…”

Section: Discussionmentioning

confidence: 95%

“…Several reports indicate that TNF mediates most of its e ects by altering the redox state of the cell (Schulze-Ostho et al, 1992;Ishi et al, 1992;Shoji et al, 1995;Goossens et al, 1995Goossens et al, , 1996Zamzami et al, 1995;Phelps et al, 1995;Mehlen et al, 1996;Obrador et al, 1997;Fernandez-Checa et al, 1997;Morales et al, 1997;Liu et al, 1998;Kinscherf et al, 1998). Some reports suggest that TNF produces ROI, which in turn oxidizes intracellular glutathione, a critical change for TNF-induced apoptosis and NFkB activation Staal et al, 1990;Shreck et al, 1991Shreck et al, , 1992aAnderson et al, 1994;Garcia-Ruiz et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Because mitochondria are the major sources of cellular ROI, the inhibitors of mitochondrial electron transport chain and respiration-de®cient cells diminish the TNF-induced signaling (Schultz-Ostho et al, 1992Shoji et al, 1995;Zamzami et al, 1995;Goossens et al, 1996;Fernandez-Checa et al, 1997;Higuchi et al, 1997). Similarly, such agents as dithiothreitol (DTT), pyrrolidine dithiocarbamate (PDTC), butylated hydroxyanisol (BHA), cysteine, and N-acetylcysteine (NAC), all of which increase extracellular GSH levels, have been shown to protect cells from TNF-induced apoptosis (Shoji et al, 1995;Goossens et al, 1995, Obrador et al, 1997Fernandez-Checa et al, 1997;Morales et al, 1997;Liu et al, 1998;Kinscherf et al, 1998) and inhibit NF-kB activation Staal et al, 1990;Schreck et al, 1991Schreck et al, , 1992aAnderson et al, 1994), whereas buthionine-L-sulfoximine (BSO), diethyl maleate (DEM), and 1,3-bis (chloroethyl)-1-nitrosourea (BCNU), which lower GSH levels potentiate the e ects of TNF (Sen et al, 1997;Obrador et al, 1997;Garcia-Ruiz et al, 1995;Higuchi et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1

1999

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Tumor necrosis factor (TNF) is a highly pleiotropic cytokine whose activity is at least partially regulated by the redox status of the cell. The cellular redox status is controlled primarily by glutathione, a major cellular antioxidant, whose synthesis is regulated by the ratelimiting enzyme g-glutamylcysteine synthetase (g-GCS).In the present report we investigated the e ect of g-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-kB and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with g-GCS cDNA blocked TNF-induced NF-kB activation, cytoplasmic IkBa degradation, nuclear translocation of p65, and NF-kB-dependent gene transcription. g-GCS overexpression also completely suppressed NF-kB activation induced by phorbol ester and okadaic acid, whereas that induced by H 2 O 2 , ceramide, and lipopolysaccharide was minimally a ected. g-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF-induced activation of JNK and mitogen-activated protein kinase kinase. TNF-mediated cytotoxicity and activation of caspase-3 were both abrogated in g-GCS-overexpressing cells. Overall, our results indicate that most of the pleiotropic actions of TNF are regulated by the glutathione-controlled redox status of the cell.

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“…A partial p53-dependent effect on cell survival has been observed in differentiated macrophages treated with these agents (Kinscherf et al, 1998). Preincubation with p53-antisense oligonucleotides reduced oxidative stress-dependent upregulation of p53 and decreased the amount of apoptosis by about 20%.…”

Section: Discussionmentioning

confidence: 97%

Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells

Pruschy¹,

Resch²,

Yq³

et al. 1999

Br J Cancer

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Summary p53 mutations are among the most common genetic alterations in human cancer and are frequently described in intrinsic or acquired radio-and chemotherapy resistance. Radiation-induced cell kill is not only mediated by DNA damage but also by the activation of signal transduction cascades generated at the plasma membrane like the sphingomyelin pathway. We used genetically defined wild-type p53 or p53-deficient mouse fibrosarcoma cells to investigate the p53-dependence of tumour response upon activation of the sphingomyelin pathway. Treatment of the tumour cells with neutral sphingomyelinase drastically reduced the amount of wild-type p53 fibrosarcoma cell proliferation over 72 h in a clear dose-response (0.2-1.0 U ml Ϫ1 nSMase). Sphingomyelinase had no effect on cell proliferation in tumour cells lacking p53. Similarly, cell proliferation was abolished by C2-ceramide (5-20 µM) only in wild-type p53 cells. FACS-analysis revealed that C2-ceramide induced massive p53-dependent apoptosis (40-50% after 12-24 h) and cell cycle analysis showed a transient G1 arrest in p53-deficient tumour cells 12-24 h after C2-ceramide exposure. These results suggest that ceramide-induced apoptosis in tumour cells can be dependent on the status of p53 and imply that p53 is also important for stress-induced apoptotic signal transduction cascades generated at the plasma membrane.

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Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent

Cited by 130 publications

References 46 publications

Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1

Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells

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