The role of p53 in neuronal cell death

Morrison, Richard S.; Kinoshita, Yoshito

doi:10.1038/sj.cdd.4400741

Cited by 159 publications

(105 citation statements)

References 158 publications

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“…Activation of p53 has been implicated in excitotoxic neuronal cell death (Morrison and Kinoshita 2000). Moreover, it has also been observed that p53 is activated under hypoxic conditions in vitro (Stempien-Otero et al 1999) and in peri-ischemic regions of an animal model of focal stroke (Chopp et al 1992;Li et al 1994).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Oligodendrocyte injury in multiple sclerosis: a role for p53

Wosik

Antel

Kuhlmann

et al. 2003

Journal of Neurochemistry

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“…Previous reports have shown that p53, at least in certain tissues, is necessary for cell death induction by ischemia. 31 However, different levels of p53 expression do not seem to be involved in the resistance to ischemia of p66…”

Section: P66mentioning

confidence: 99%

p66 ^ShcA Modulates Tissue Response to Hindlimb Ischemia

et al. 2004

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Background— Oxidative stress plays a pivotal role in ischemia and ischemia/reperfusion injury. Because p66 ShcA -null (p66 ShcA −/−) mice exhibit both lower levels of intracellular reactive oxygen species and increased resistance to cell death induced by oxidative stress, we investigated whether tissue damage that follows acute ischemia or ischemia/reperfusion was altered in p66 ShcA −/− mice. Methods and Results— Unilateral hindlimb ischemia was induced by femoral artery dissection, and ischemia/reperfusion was induced with an elastic tourniquet. Both procedures caused similar changes in blood perfusion in p66 ShcA wild-type (p66 ShcA wt) and p66 ShcA −/− mice. However, significant differences in tissue damage were found: p66 ShcA wt mice displayed marked capillary density decrease and muscle fiber necrosis. In contrast, in p66 ShcA −/− mice, minimal capillary density decrease and myofiber death were present. When apoptosis after ischemia was assayed, significantly lower levels of apoptotic endothelial cells and myofibers were found in p66 ShcA −/− mice. In agreement with these data, both satellite muscle cells and endothelial cells isolated from p66 ShcA −/− mice were resistant to apoptosis induced by simulated ischemia in vitro. Lower apoptosis levels after ischemia in p66 ShcA −/− cells correlated with decreased levels of oxidative stress both in vivo and in vitro. Conclusions— p66 ShcA plays a crucial role in the cell death pathways activated by acute ischemia and ischemia/reperfusion, indicating p66 ShcA as a potential therapeutic target for prevention and treatment of ischemic tissue damage.

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“…In the central nervous system, however, replacement neurons are only available marginally if at all (3,4), putting a greater burden on the survival mechanisms of mature neurons. Determining how neurons are able to survive manyfold longer than the average mammalian cell poses one of the great challenges of research in neurobiology (5,6). This question is more than of academic interest because failure to survive, either during the developmental process, during aging, or upon exposure to potentially lethal insults, is the basis for innumerable neurodegenerative conditions.…”

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confidence: 99%

Muscarinic Receptor Activation Protects Cells from Apoptotic Effects of DNA Damage, Oxidative Stress, and Mitochondrial Inhibition

Sarno

Shestopal

King

et al. 2003

Journal of Biological Chemistry

107

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The impact of muscarinic receptor stimulation was examined on apoptotic signaling induced by DNA damage, oxidative stress, and mitochondrial impairment. Exposure of human neuroblastoma SH-SY5Y cells to the DNA-damaging agent camptothecin increased p53 levels, activated caspase-3, and caused cell death. Pretreatment with oxotremorine-M, a selective agonist of muscarinic receptors that are expressed endogenously in these cells, did not affect the accumulation of p53 but greatly attenuated caspase-3 activation and protected from cell death to nearly the same extent as treatment with a general caspase inhibitor. Treatment with 50 -200 M H 2 O 2 caused the activation of caspase-3 beginning after 2-3 h, followed by eventual cell death. Oxotremorine-M pretreatment protected cells from H 2 O 2 -induced caspase-3 activation and death, and this was equivalent to protection afforded by a caspase inhibitor. Muscarinic receptor stimulation also protected cells from caspase-3 activation induced by exposure to rotenone, a mitochondrial complex 1 inhibitor, but no protection was evident from staurosporine-induced caspase-3 activation. The mechanism of protection afforded by muscarinic receptor activation from camptothecin-induced apoptotic signaling involved blockade of mitochondrial cytochrome c release associated with a bolstering of mitochondrial bcl-2 levels and blockade of the translocation of Bax to mitochondria. Likely the most proximal of these events to muscarinic receptor activation, mitochondrial Bax accumulation, also was attenuated by oxotremorine-M treatment after treatment with H 2 O 2 or rotenone. These results demonstrate that stimulation of muscarinic receptors provides substantial protection from DNA damage, oxidative stress, and mitochondrial impairment, insults that may be encountered by neurons in development, aging, or neurodegenerative diseases. These findings suggest that neurotransmitter-induced signaling bolsters survival mechanisms, and inadequate neurotransmission may exacerbate neuronal loss.

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The role of p53 in neuronal cell death

Cited by 159 publications

References 158 publications

Oligodendrocyte injury in multiple sclerosis: a role for p53

Oligodendrocyte injury in multiple sclerosis: a role for p53

p66 ^ShcA Modulates Tissue Response to Hindlimb Ischemia

Muscarinic Receptor Activation Protects Cells from Apoptotic Effects of DNA Damage, Oxidative Stress, and Mitochondrial Inhibition

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The role of p53 in neuronal cell death

Cited by 159 publications

References 158 publications

Oligodendrocyte injury in multiple sclerosis: a role for p53

Oligodendrocyte injury in multiple sclerosis: a role for p53

p66 ShcA Modulates Tissue Response to Hindlimb Ischemia

Muscarinic Receptor Activation Protects Cells from Apoptotic Effects of DNA Damage, Oxidative Stress, and Mitochondrial Inhibition

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Product

Resources

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p66 ^ShcA Modulates Tissue Response to Hindlimb Ischemia