2001
DOI: 10.1523/jneurosci.21-14-05045.2001
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Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death

Abstract: After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16INK4a is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27 Kip1 , another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxyge… Show more

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Cited by 219 publications
(183 citation statements)
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“…[106][107][108] This correlated exactly to the time window at which caspase inhibitors are able to protect the ischemic brain. 107 Also, there is evidence of abortive cell cycle re-entry as a prelude to delayed neuronal death 109 : dying neurons exhibit an early loss of endogenous cyclin-dependent kinases such as p16, which is followed by upregulation of cycling D1, activation of cyclin-dependent kinases, and subsequent cell death. A small fraction of dying neurons even seems to enter S phase before delayed cell death demonstrated by uptake of bromodeoxyuridine in TUNEL-positive cells.…”
Section: Animal Modelsmentioning
confidence: 99%
See 1 more Smart Citation
“…[106][107][108] This correlated exactly to the time window at which caspase inhibitors are able to protect the ischemic brain. 107 Also, there is evidence of abortive cell cycle re-entry as a prelude to delayed neuronal death 109 : dying neurons exhibit an early loss of endogenous cyclin-dependent kinases such as p16, which is followed by upregulation of cycling D1, activation of cyclin-dependent kinases, and subsequent cell death. A small fraction of dying neurons even seems to enter S phase before delayed cell death demonstrated by uptake of bromodeoxyuridine in TUNEL-positive cells.…”
Section: Animal Modelsmentioning
confidence: 99%
“…A small fraction of dying neurons even seems to enter S phase before delayed cell death demonstrated by uptake of bromodeoxyuridine in TUNEL-positive cells. 109 In contrast, however, electron microscopic imaging failed to demonstrate bona fide apoptotic morphology (Auer and Endres, unpublished observation).…”
Section: Animal Modelsmentioning
confidence: 99%
“…For example, although transient middle cerebral artery occlusion (MCAO) induces aberrant cell cycle reentry, the incorporation of a thymidine analog, bromodeoxyuridine (BrdU), is only found in Ͻ1% of the terminal deoxynucleotidyl transferasemediated biotinylated UTP nick end labeling (TUNEL)-positive cells (Katchanov et al, 2001;Wen et al, 2004). One interpretation of the small percentage of TUNEL-and BrdU-doublelabeled cells is that most neurons are inherently incapable of passing the G 1 /S-phase checkpoint even after reentering the cellcycle.…”
Section: Introductionmentioning
confidence: 99%
“…Treatment with a cyclin‐dependent kinase inhibitor can significantly reduce cell death in vitro 26. Our study showed that, compared with the sham group, the protein expression level of CYCLIN was significantly downregulated in the vehicle group ( P  < 0.05); and compared with the vehicle group, it was significantly downregulated in the JU group ( P  < 0.01; Supplementary Figure S5a ).…”
Section: Resultsmentioning
confidence: 73%