Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle.

Gill, Jagjit S.; Windebank, Anthony J.

doi:10.1172/jci1130

Cited by 257 publications

(147 citation statements)

References 71 publications

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“…Our present data suggest that one pathway may be through the phosphorylation of pRb. Consistent with this, it has been reported that pRb phosphorylation has been observed in in vitro cultured neurons exposed to apoptotic stress (12,19,36) and that overexpression of pRb is protective in models of embryonic cortical death evoked by DNA damage (13). In addition, there is increased developmental neuronal death in pRb-deficient mice (37,38).…”

Section: Discussionsupporting

confidence: 65%

Cyclin-dependent kinases as a therapeutic target for stroke

Osuga

Wang

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

267

221

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Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4͞cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.T he mechanism by which stroke-induced neuronal death occurs is complex and is likely dependent upon the severity and duration of ischemic insult and an elaborate interplay between ischemic death initiators such as excitotoxicity, oxidative stress, DNA damage, and inflammatory responses (1-3). Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1-3). This delayed cell death is dependent upon selected death-signaling elements such as caspases, poly(ADP-ribose) polymerase, and p53 (4). The identification of signaling molecules that control delayed neuronal death has led to the hope that some of these death-signaling elements may serve as useful therapeutic targets for the reduction of neuropathology and behavioral deficits associated with stroke injury. The mechanism by which stroke-evoked delayed death occurs, however, is not fully understood.The cell cycle is a highly coordinated process regulated by the appropriate and timely activation of cyclin-dependent kinases (CDKs) (5). Regulation of CDKs is complex and includes binding to their obligate cyclin partner, activating and inhibitory phosphorylation events, and endogenous inhibitors of CDK activity. Distinct CDKs regulate progressive phases of the cell cycle. Generally, it is thought that the Cdk4͞6͞cyclin D1 complex regulates the G 0 to G 1 , Cdk2͞cyclin E and Cdk3 control G 1 to S, and Cdk2͞cyclin A and Cdk1͞cyclin B control G 2 and M progressions. Although the downstream targets of CDKs are not fully characterized, one important substrate is the tumor suppresser retinoblastoma protein (pRb), which is phosphorylated by activated Cdk4͞6͞cyclin D complex (6). Once hyperphosphorylated, pRb is released from the transcription factor complex E2F͞DP, which then activates genes required for S phase transition (7-9).Paradoxically, increasing evidence suggests that CDKs may have functions beyond that of cell cycle regulation. Numerous reports indicate the requirement of CDK signals for death of cultured postmitotic neurons exposed to select death insults. For example, inappropriate cyclin B and cyclin D1 transcripts have been observed in neuronal P...

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Section: Discussionsupporting

confidence: 65%

Cyclin-dependent kinases as a therapeutic target for stroke

Osuga

Wang

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

267

221

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“…18 Since then, neuronal levels of cyclin D1 transcripts and/or protein have been reported to be elevated in response to a wide range of apoptotic stimuli in vitro, in vivo and in neurodegenerative diseases. For culture systems, this includes cerebellar granule neurons switched from culture medium containing depolarizing levels of K þ to one containing low levels of K þ 26-29 (we shall henceforth refer to this model as 'repolarization'), cerebellar granule neurons exposed to kainic acid, 30 cortical neurons exposed to beta amyloid protein, 31 sensory neurons exposed to cisplatin 32 and serum-deprived neuroblastoma cells. 33 In the repolarization model, the distribution of cyclin D1 also appeared to change from a diffuse cytoplasmic pattern to a nuclear localization.…”

Section: Cyclin D1mentioning

confidence: 99%

“…Stimuli including camptothecin, 92 cisplatin, 32 beta amyloid, 31 repolarization 27,68 and proteasome inhibitors 73 promote pRb phosphorylation in cultured neurons. Similar findings pertain to p107.…”

Section: Rb/pocket Proteins and Neuron Deathmentioning

confidence: 99%

Cell cycle molecules and vertebrate neuron death: E2F at the hub

2003

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Vertebrate neuron cell death is both a normal developmental process and the catastrophic outcome of nervous system trauma or degenerative disorders. Although the mechanisms of such death include an evolutionarily conserved core apoptotic pathway that is highly homologous to that first described by Horvitz and co-workers in Caenorhabditis elegans, it appears that many instances of neuron death additionally require the transcription-dependent induction of proapoptotic molecules. One such proapoptotic transcriptional pathway revealed by studies over the past decade revolves about the transcription factor E2F and those molecules that either regulate E2F activity or that are direct or indirect transcriptional targets of E2F. Many of the molecules associated with the E2F apoptotic pathway in postmitotic neurons also participate in the cell cycle in proliferating cells. Observations in human material and in animal and cell culture models show widespread correlation between changes in expression, activity and subcellular localization of E2F-related cell cycle molecules and developmental and catastrophic neuron death. A variety of experimental approaches support a causal role for such changes in the death process and are beginning to indicate how the neuronal E2F pathway activates the core apoptotic machinery. The discovery and elaboration of the neuronal apoptotic E2F pathway provides abundant targets as well as small molecule candidates for potential therapeutic intervention in nervous system trauma and degenerative disease.

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“…[7,28]. In addition, MAPK kinase pathways including Cisplatin has been reported to induce apoptosis in neuronal extracellular signal-regulated kinase (ERK), c-JUN aminocells [1,5,10,12,18,20]. However, its precise signaling terminal protein kinase (JNK) and p38 MAPK were mechanism involved in cisplatin-induced apoptosis is not reported to be involved in signaling pathway induced by fully understood.…”

Section: Introductionmentioning

confidence: 99%