Nuclear accumulation of p53 protein following kainic acid-induced seizures

Sakhi, Shahin; Sun, Ning; Wing, Lauren L.; Mehta, Pareen; Schreiber, Sidney S.

doi:10.1097/00001756-199601310-00028

Cited by 83 publications

(40 citation statements)

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“…Our observations are consistent with previous reports demonstrating only nuclear p53 immunoreactivity in neurons destined to die (Wood and Youle, 1995;Hughes et al, 1996;Sakhi et al, 1996;Cregan et al, 2004). It remains to be determined, however, whether these results are universally applicable to all types of neurons, developmental stages, and all types of apoptotic stress as several reports have described cytoplasmic p53 accumulation in neurons (LaFerla et al, 1996;Sadoul et al, 1996;Jiang et al, 1998;Dietrich et al, 2003;Endo et al, 2006).…”

Section: Determinants Of P53 Localization In Neuronssupporting

confidence: 92%

Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons

Uo¹,

Kinoshita²,

Morrison³

2007

J. Neurosci.

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Recent studies in non-neuronal cells have shown that the tumor suppressor p53 can promote cell death through a transcriptionindependent mechanism involving its direct action with a subset of Bcl-2 family member proteins in the cytosol and at the mitochondria. In cultured cortical neurons, however, we could not find evidence supporting a significant contribution of the cytosolic/mitochondrial p53 pathway, and available evidence instead corroborated the requirement for the transcriptional activity of p53. When directly targeted to the cytosol/mitochondria, wild-type p53 lost its apoptosis-inducing activity in neurons but not in non-neuronal cells. The N-terminal p53 fragment (transactivation and proline-rich domains), which induces apoptosis in non-neuronal cells via the cytosolic/mitochondrial pathway, displayed no apoptogenic activity in neurons. In neuronal apoptosis induced by camptothecin or an MDM2 (murine double minute 2) inhibitor, nutlin-3, endogenous p53 protein did not accumulate in the cytosol/mitochondria, and transcriptional inhibition after p53 induction effectively blocked cell death. In addition, overexpression of a dominant-negative form of p53 (R273H) completely suppressed induction of proapoptotic p53 target genes and cell death. PUMA (p53-upregulated modulator of apoptosis) was one such gene induced by camptothecin, and its overexpression was sufficient to induce Bax (Bcl-2-associated X protein)-dependent neuronal death, whereas Noxa was not apoptogenic. These results collectively demonstrate that, in contrast to non-neuronal cells, the apoptotic activity of p53 in postnatal cortical neurons does not rely on its direct action at the cytosol/mitochondria but is exclusively mediated through its transcription-dependent functions. The uniqueness of p53-mediated apoptotic signaling in postnatal cortical neurons was further illustrated by the dispensable function of the proline-rich domain of p53.

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Section: Determinants Of P53 Localization In Neuronssupporting

confidence: 92%

Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons

Uo¹,

Kinoshita²,

Morrison³

2007

J. Neurosci.

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“…A second possibility is that premitochondrial caspases (Steemans et al, 1998) might be activated in neurons exposed to homocysteine. A role for p53 in homocysteine-induced, PARP-mediated neuronal apoptosis is consistent with considerable data implicating p53 in neuronal deaths that occur in experimental models of excitotoxic and ischemic brain injury (Sakhi et al, 1996;McGahan et al, 1998;Xiang et al, 1998).…”

Section: Discussionsupporting

confidence: 82%

Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity

et al. 2000

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Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.

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“…Further, neuronal dysfunction can also involve chronic oxidative stress that could cause sub-lethal DNA damage and activate p53, which in turn induces caspases in axons and dendrites under extensive simulation by excitatory neurotransmitters, a phenomenon that could result in synaptic cell death and dendritic thinning [100] . Other byproducts of the HIV-induced immune activation, such as kainic acid and quinolinic acid, are known to inflict morphological damage to neurons and induce p53 expression in neurons [109,110] .…”

Section: Role Of P53 In Neurodegenerative Diseasesmentioning

confidence: 99%

Role of p53 in Neurodegenerative Diseases

Ghafouri²,

et al. 2011

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Background: p53 plays an important role in many areas of cellular physiology and biology, ranging from cellular development and differentiation to cell cycle arrest and apoptosis. Many of its functions are attributed to its role in assuring proper cellular division. However, since the establishment of its role in cell cycle arrest, damage repair, and apoptosis (thus also establishing its importance in cancer development), numerous reports have demonstrated additional functions of p53 in various cells. In particular, p53 appears to have important functions as it relates to neurodegeneration and synaptic plasticity. Objective: In this review, we will address p53 functions as it relates to various neurodegenerative diseases, mainly its implications in the development of HIV-associated neurocognitive disorders. Conclusion: p53 plays a pivotal role in the development of neurodegenerative diseases through its interaction with cellular factors, viral factors, and/or small RNAs that have the ability to promote the development of these diseases. Hence, inhibition of p53 may present an ideal target to restore neuronal functions.

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Nuclear accumulation of p53 protein following kainic acid-induced seizures

Cited by 83 publications

References 0 publications

Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons

Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons

Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity

Role of p53 in Neurodegenerative Diseases

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