Antiapoptotic effects of roscovitine in cerebellar granule cells deprived of serum and potassium: a cell cycle-related mechanism

Verdaguer, Ester; Jordà, Elvira G.; Canudas, Anna Maria; Jiménez, Andrés; Piccoli, David A.; Escubedo, Elena; Camarasa, Jorge; Pallàs, Mercè; Camins, Antoni

doi:10.1016/s0197-0186(03)00147-5

Cited by 32 publications

(14 citation statements)

References 68 publications

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“…These data were further substantiated by our finding that the selective CDK1/CDK2 inhibitor roscovitine efficiently prevented IR-induced caspase-9 and caspase-3 processing and activation in p21-deficient cells but had no effect on caspase-2 processing or the loss of DW m induced by this treatment. Inhibition of apoptosis by CDK inhibitors, such as roscovitine or structurally related compounds, was also observed in several other cellular systems; the underlying events that were affected by these treatments, however, were not further investigated (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

Sohn¹,

Eßmann²,

et al. 2006

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The role of the cyclin-dependent kinase (CDK) inhibitor p21 as a mediator of p53-induced growth arrest is well established. In addition, recent data provide strong evidence for new emerging functions of p21, including a role as a modulator of apoptosis. The mechanisms, however, by which p21 interferes with the death machinery, especially following ionizing radiation (IR), are largely unknown. Here, we report that IR induced caspase-9 and caspase-3 activation and subsequent apoptosis only in p21-deficient colon carcinoma cells, whereas similar treated wild-type cells were permanently arrested in the G 2 -M phase, correlating with the induction of cellular senescence. Interestingly, activation of the mitochondrial pathway, including caspase-2 processing, depolarization of the outer mitochondrial membrane, and cytochrome c release, was achieved by IR in both cell lines, indicating that p21 inhibits an event downstream of mitochondria but preceding caspase-9 activation. IR-induced p21 protein expression was restricted to the nucleus, and no evidence for a mitochondrial or cytoplasmic association was found. In addition, p21 did neither interact with caspase-3 or caspase-9, suggesting that these events are not required for the observed protection. Consistent with this assumption, we found that CDK inhibitors potently abrogated IR-induced caspase processing and activation without affecting mitochondrial events. In addition, in vitro caspase activation assays yielded higher caspase-3 activities in extracts of irradiated p21-deficient cells compared with extracts of similar treated wild-type cells. Thus, our results strongly indicate that p21 protects cells from IR-induced apoptosis by suppression of CDK activity that seems to be required for activation of the caspase cascade downstream of the mitochondria. (Cancer Res 2006; 66(23): 11254-62)

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Section: Discussionmentioning

confidence: 99%

p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

Sohn¹,

Eßmann²,

et al. 2006

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“…We evaluated cell-cycle progression by monitoring the incorporation of BdrU into the cells cultured in microtiter plates [41]. Following partial denaturation of doublestranded DNA, BdrU was detected immunochemically, which allowed us to count the cells that synthesize DNA.…”

Section: Evaluation Of Dna Synthesis: Brdu Labelingmentioning

confidence: 99%

“…6a). In addition, S/K withdrawal was used as positive control of BrdU incorporation, as we have demonstrated in previous studies [41]. Thus MPP ?…”

Section: Ku-55933 Inhibits Mpp ? -Induced Apoptosis In Cgcmentioning

confidence: 99%

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

Camins

Pizarro

Alvira

et al. 2010

Cell. Mol. Life Sci.

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In the present study we demonstrated that neurotoxin MPP(+)-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP(+)-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson's disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G(0)/G(1) cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP(+) leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP(+) and cell-cycle re-entry through retinoblastoma protein phosphorylation.

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“…For example, a recent study suggests that Cdk5/p35 suppresses the reentry of neurons into the cell cycle by disrupting the cell cycle regulatory transcriptional complex [8] . On the other hand, hyperactivation of Cdk5 by p25, a proteolytic cleavage product of p35 during neuronal apoptosis, leads to abnormal activation of cell cycle reentry [20,21] . Thus, tight control of Cdk5 activity is important for the gene regulation of cell cycle proteins in both neuronal survival and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 Phosphorylates a Component of the HDAC Complex and Regulates Histone Acetylation during Neuronal Cell Death

Hung²,

Wong³

et al. 2013

Neurosignals

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Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for regulating neural development and neuronal survival. Dysregulation of Cdk5 is associated with abnormal expression of cell cycle-related proteins during neuronal apoptosis. We have previously found that p35, a Cdk5 activator, interacts with mSds3, an integral component of the histone deacetylase complex in vitro, suggesting a functional role of Cdk5 in gene regulation through modulation of chromatin integrity. In this study, we further demonstrate that Cdk5-dependent phosphorylation of mSds3 at Ser228 occurs in mouse brain nuclei. The expression of mSds3 protein and its interaction with Cdk5 activators is developmentally regulated in the mouse brain. Importantly, our findings suggest that the ability of Cdk5 to regulate activity deprivation-induced apoptosis of cerebellar granule neurons is likely mediated by the regulation of histone acetylation. Suppression of Cdk5 not only attenuates the induction of histone H3 acetylation and the aberrant upregulation of cyclin proteins in neurons after activity deprivation, but also results in protection of neurons against apoptotic cell death. Taken together, our findings suggest that Cdk5 regulates neuronal survival by precise epigenetic control through modulation of histone acetylation.

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Antiapoptotic effects of roscovitine in cerebellar granule cells deprived of serum and potassium: a cell cycle-related mechanism

Cited by 32 publications

References 68 publications

p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

Cdk5 Phosphorylates a Component of the HDAC Complex and Regulates Histone Acetylation during Neuronal Cell Death

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