Dopamine Neurons from Transgenic Mice with a Knockout of the p53 Gene Resist MPTP Neurotoxicity

Trimmer, Patricia A.; Smith, Trisha S.; Jung, Anthony B.; Bennett, James P.

doi:10.1006/neur.1996.0031

Cited by 129 publications

(78 citation statements)

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“…p53 has also been previously shown to be important for neuronal death under many circumstances (for example, Refs. [41][42][43]. In addition, several reports have indicated that p53 stability and transactivational capacity is directly modulated by JNKs (25,26).…”

Section: Jnk3 Modulates Death Of Facial Motormentioning

confidence: 99%

c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation

Keramaris

Vanderluit

Bahadori

et al. 2005

Journal of Biological Chemistry

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Section: Jnk3 Modulates Death Of Facial Motormentioning

confidence: 99%

c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation

Keramaris

Vanderluit

Bahadori

et al. 2005

Journal of Biological Chemistry

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“…Cells-A previous study showed that dopamine neurons from p53 knock-out mice are resistant to MPTP neurotoxicity (27), suggesting that MPP ϩ -induced apoptosis is at least partly mediated by p53 (28). To dissect the p53-independent effect of MPP ϩ , we first examined whether MPP ϩ suppresses the growth of p53-deficient MG63 osteosarcoma cells.…”

Section: Mpp ϩ Suppresses the Cell Growth Of P53-deficient Mg63mentioning

confidence: 99%

Proteasome-dependent Degradation of Cyclin D1 in 1-Methyl-4-phenylpyridinium Ion (MPP+)-induced Cell Cycle Arrest

Bai

Nakamura

Ueda

et al. 2004

Journal of Biological Chemistry

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1-Methyl-4-phenylpyridinium ion (MPP ؉), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP ؉ inhibits cell proliferation is still unclear. In this study, we found that MPP ؉ suppressed the proliferation with accumulation in G 1 phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP ؉ induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP ؉ was also observed in p53-positive PC12, HeLa S3, and HeLa 0 cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP ؉ dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3␤ inhibitor, suppressed the cyclin D1 down-regulation caused by MPP ؉ . Our results demonstrate that MPP ؉ induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome-and phosphatidylinositol 3-Akt-glycogen synthase kinase-3␤-dependent cyclin D1 degradation.1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 1 is commonly used in animals to produce an experimental model of Parkinson's disease (1, 2). 1-Methyl-4-phenylpyridinium ion (MPP ϩ ) (3), an active metabolite of MPTP, induces cell death and inhibition of proliferation not only in neuronal cells but also in other types of cell (4 -7). The mechanisms whereby MPP ϩ induces the inhibition of membrane-bound NADH dehydrogenase in mitochondrial complex I (8 -10), ATP depletion (11), and production of the superoxide radicals (12, 13) have been studied extensively. However, the mechanisms involved in the inhibition of cell proliferation by MPP ϩ have rarely been examined.Progression and transition in the cell cycle of mammalian cells are governed by cyclin-dependent kinases (Cdks) whose activities are regulated by the binding of their regulatory subunits (called cyclins) or Cdk inhibitors (14). p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6, which have a direct role in the G 1 /S transition, but it is a poor inhibitor of other known Cdks (15-17). Cyclin proteolysis is essential for cell cycle progression (18,19). Cyclin D1 regulates G 1 arrest and the phosphorylation status of retinoblastoma protein (Rb). Cyclin D1 degradation is mediated by phosphorylation-triggered, ubiquitin-dependent proteolysis (20). Cyclin D1 proteolysis is regulated by glycogen synthase kinase-3␤ (GSK-3␤) (21), which is inactivated by a pathway that sequentially involves Ras, phosphatidylinositol 3-kinase (PI3K), and Akt (22).The aim of this study was to examine the mechanisms whereby MPP ϩ inhibits cell proliferation. We show here that MPP ϩ initiates an efficient p53-...

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“…This genome surveillance function of p53 is also critical in neurons (10 -13). In this regard, p53 is activated and required for neuronal injury induced by DNA-damaging agents (14,15), excitotoxicity (11,16) dopaminergic toxins (4), and ischemia (12). Although this evidence exemplifies the importance of p53 in neuronal death, the signals that link DNA damage to p53 induction and activation are not clear.…”

mentioning

confidence: 97%

“…DNA damage is an important initiator of neuronal death and has been implicated in a wide variety of neuropathological conditions such as stroke (1, 2), Parkinson's disease (3)(4)(5), and Huntington's disease (6). In addition, direct loss and impairment of neurons caused by chemotherapeutic agents has also been described (7)(8)(9).…”

mentioning

confidence: 99%

Ataxia Telangiectasia-mutated Protein Can Regulate p53 and Neuronal Death Independent of Chk2 in Response to DNA Damage

Keramaris

Hirao

Slack

et al. 2003

Journal of Biological Chemistry

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DNA damage is a key initiator of neuronal death. We have previously shown that the tumor suppressor p53, in conjunction with cyclin-dependent kinases (CDKs), regulates the mitochondrial pathway of death in neurons exposed to genotoxic agents. However, the mechanisms by which p53 is regulated is unclear. Presently, we show that p53 is phosphorylated on Ser-15 following DNA damage and this occurs independently of the CDK pathway. Instead, we show that p53 phosphorylation, stability, as well as neuronal death is regulated, in part, by the ataxia telangiectasia-mutated (ATM) protein.Previous reports have suggested that ATM regulation of p53 occurs through Chk2. However, in our present paradigms, we show that ATM functions separately from Chk2 to regulate p53 stability and neuronal death. Chk2 deficiency does not affect p53 stability or neuronal death induced by Topoisomerase I or II inhibition. Taken together, our results provide a model by which DNA damage can activate an ATM-dependent, Chk2-independent pathway of p53-mediated neuronal death.

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Dopamine Neurons from Transgenic Mice with a Knockout of the p53 Gene Resist MPTP Neurotoxicity

Cited by 129 publications

References 0 publications

c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation

c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation

Proteasome-dependent Degradation of Cyclin D1 in 1-Methyl-4-phenylpyridinium Ion (MPP+)-induced Cell Cycle Arrest

Ataxia Telangiectasia-mutated Protein Can Regulate p53 and Neuronal Death Independent of Chk2 in Response to DNA Damage

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