p53 Induction by Tumor Necrosis Factor‐α and Involvement of p53 in Cell Death of Human Oligodendrocytes

Ladiwala, Uma; Li, Hewei; Antel, Jack P.; Nalbantoglu, Joséphine

doi:10.1046/j.1471-4159.1999.0730605.x

Cited by 53 publications

(52 citation statements)

References 34 publications

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“…In a previous report, we showed that exposure of human adult OLs to the pro-inflammatory cytokine TNFa was associated with the up-regulation and nuclear translocation of the tumor-suppressor gene p53, a major regulator of apoptotic pathways. We also showed that overexpressing p53 in human adult OLs in culture induces rapid apoptosis in these cells (Ladiwala et al 1999).…”

mentioning

confidence: 70%

“…The protocol was approved by an institutional review board according to the guidelines of the Canadian Institutes for Health Research. OLs were isolated as previously described (D'Souza et al 1996;Ladiwala et al 1999;Pouly et al 2000). Briefly, brain tissue was dissociated enzymatically with trypsin and DNAse, and mechanically by passage through a 132-lm nylon mesh.…”

Section: Methodsmentioning

confidence: 99%

“…Such stimuli include inflammatory cytokines/inflammation (Brysk et al 1995;Krishna et al 1995;Yeung and Lau 1998;Ladiwala et al 1999;Rokhlin et al 2000), ischemia/hypoxia (Banasiak and Haddad 1998;StempienOtero et al 1999;Watanabe et al 1999), trauma (Kaya et al 1999) and viral infection (Everett and McFadden 1999;Genini et al 2001) all of which have been established or postulated to be involved in the initiation and/or evolution of the MS disease process (Noseworthy 1999). p53 mediates its effects by modulating the expression of key cellular genes (Hansen and Oren 1997;Evan and Littlewood 1998).…”

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confidence: 99%

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Oligodendrocyte injury in multiple sclerosis: a role for p53

Wosik

Antel

Kuhlmann

et al. 2003

Journal of Neurochemistry

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Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.

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confidence: 70%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Oligodendrocyte injury in multiple sclerosis: a role for p53

Wosik

Antel

Kuhlmann

et al. 2003

Journal of Neurochemistry

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“…The concentration of TNF-␣ was based on the consideration that these concentrations best mimic a pathological condition similar to the one present in vivo. In addition, the use of this concentration for treatments of oligodendrocyte-derived cell cul-tures and primary oligodendrocytes has been documented by several previous studies (Hisahara et al, 1997;Ladiwala et al, 1999;Ye and D'Ercole, 1999;Cammer, 2000;Buntinx et al, 2004b). The cells were harvested by trypsinization, and the cells that could not be trypsinized were scraped off in cold PBS containing proteinase inhibitor mixture.…”

Section: Methodsmentioning

confidence: 99%

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

Mastronardi¹,

Wood²,

Jiang³

et al. 2006

J. Neurosci.

228

175

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Modification of arginine residues by citrullination is catalyzed by peptidylarginine deiminases (PADs), of which five are known, generating irreversible protein structural modifications. We have shown previously that enhanced citrullination of myelin basic protein contributed to destabilization of the myelin membrane in the CNS of multiple sclerosis (MS) patients. We now report increased citrullination of nucleosomal histones by PAD4 in normal-appearing white matter (NAWM) of MS patients and in animal models of demyelination. Histone citrullination was attributable to increased levels and activity of nuclear PAD4. PAD4 translocation into the nucleus was attributable to elevated tumor necrosis factor-␣ (TNF-␣) protein. The elevated TNF-␣ in MS NAWM was not associated with CD3 ϩ or CD8 ϩ lymphocytes, nor was it associated with CD68 ϩ microglia/macrophages. GFAP, a measure of astrocytosis, was the only cytological marker that was consistently elevated in the MS NAWM, suggesting that TNF-␣ may have been derived from astrocytes. In cell cultures of mouse and human oligodendroglial cell lines, PAD4 was predominantly cytosolic but TNF-␣ treatment induced its nuclear translocation. To address the involvement of TNF-␣ in targeting PAD4 to the nucleus, we found that transgenic mice overexpressing TNF-␣ also had increased levels of citrullinated histones and elevated nuclear PAD4 before demyelination. In conclusion, high citrullination of histones consequent to PAD4 nuclear translocation is part of the process that leads to irreversible changes in oligodendrocytes and may contribute to apoptosis of oligodendrocytes in MS.

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“…Although as a proinflammatory cytokine TNF␣ often opposes p53 activity (62), it has been shown to induce p53 and increase p53-dependent apoptosis (63). Conversely p53 may increase TNF␣-dependent apoptosis through induction of a proapoptotic factor (64) or indirectly regulate TNF␣ signaling through the GR.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes posttranslationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53 K317R knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53 K317R thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53 K317R samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53 K317R mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R thymocytes as well as a decrease in tumor necrosis factor ␣ signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between

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p53 Induction by Tumor Necrosis Factor‐α and Involvement of p53 in Cell Death of Human Oligodendrocytes

Abstract: Oligodendrocytes (OLs) and their myelin mem-

Cited by 53 publications

References 34 publications

Oligodendrocyte injury in multiple sclerosis: a role for p53

Oligodendrocyte injury in multiple sclerosis: a role for p53

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

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