Cdc2 Phosphorylation of BAD Links the Cell Cycle to the Cell Death Machinery

Konishi, Yoshiyuki; Lehtinen, Maria K.; Donovan, Nicole; Bonni, Azad

doi:10.1016/s1097-2765(02)00524-5

Cited by 269 publications

(283 citation statements)

References 46 publications

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“…As apoptosis is also suppressed by Wnt signaling (Figure 3c), it is conceivable that these cells enter the next cycle even if they are polyploid (>4N) or aneuploid. This interpretation is consistent with the reports that inhibition of Cdc2 through its phosphorylation at Y15 suppresses paclitaxelinduced apoptosis (Konishi et al, 2002;Tan et al, 2002). These results may explain the increased ABI by Wnt signaling activation (Figure 1).…”

Section: Es Cells With High Abi Produce New Chromosomal Aberrationssupporting

confidence: 93%

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate b-catenin/ T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or b-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signalactivated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear b-catenin, ABI was significantly higher than in those without. These results collectively indicate that b-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Section: Es Cells With High Abi Produce New Chromosomal Aberrationssupporting

confidence: 93%

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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“…There also may be a different accessibility to substrates of cyclin B/CDK1 that would change the outcome of its activity. For example, the pro-apoptotic protein BAD is phosphorylated by cyclin B1/CDK1 both in vitro and in vivo during apoptosis in postmitotic neurons (Konishi et al, 2002). We were unable to detect Bad phosphorylation in our model.…”

Section: Discussionmentioning

confidence: 55%

Analysis of cyclin B1 and CDK activity during apoptosis induced by camptothecin treatment

et al. 2006

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We have studied the role of cyclins and cyclin-dependent kinase (CDK) activity in apoptosis induced by camptothecin (CPT). In this model, 22% of the cells stain for annexin-V at 24 h and then proceed to be 93% positive by 72 h. This time window permits the analysis of cyclins in cells that are committed to apoptosis but not yet dead. We provide evidence that cyclin protein levels and then associated kinase levels increase after CPT treatment. Strikingly, cyclin B1 and cyclin E1 proteins are present at the same time in CPT treated HT29 cells. Although cyclin B1 and E1 CDK complexes are activated in CPT treated cells, only the cyclin B1 complex is required for apoptosis since reduction of cyclin B1 by RNAi or roscovitine treatment reduces the number of annexin-V-stained cells. We have detected poorly organized chromosomes and phosphorylated histone H3 epitopes at the time of maximum cyclin B1/CDK kinase activity in CPT-treated cells, which suggests that these cells enter a mitotic catastrophe. Understanding which CDKs are required for apoptosis may allow us to better adapt CDK inhibitors for use as anti-cancer compounds.

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“…This site can be phosphorylated by the cyclin-dependent kinase Cdc2 and by JNKs. 55,56 In developing rat CGNs cultured in vitro Cdc2 kinase activity increases after KCl deprivation and promotes apoptosis of these neurons. 55 Cdc2 phosphorylates Bad at serine 128 in cell free assays and in neurons in culture, and this phosphorylation inhibits the interaction of Bad phosphorylated by growth factor treatment with 14-3-3 proteins.…”

Section: Post-translational Regulation Of Bim and Bad By Phosphorylationmentioning

confidence: 99%

“…55,56 In developing rat CGNs cultured in vitro Cdc2 kinase activity increases after KCl deprivation and promotes apoptosis of these neurons. 55 Cdc2 phosphorylates Bad at serine 128 in cell free assays and in neurons in culture, and this phosphorylation inhibits the interaction of Bad phosphorylated by growth factor treatment with 14-3-3 proteins. 55 JNKs can also phosphorylate Bad at serine 128 in vitro and in cultured CGNs and again this promotes the apoptotic effect of Bad.…”

Section: Post-translational Regulation Of Bim and Bad By Phosphorylationmentioning

confidence: 99%

“…55 Cdc2 phosphorylates Bad at serine 128 in cell free assays and in neurons in culture, and this phosphorylation inhibits the interaction of Bad phosphorylated by growth factor treatment with 14-3-3 proteins. 55 JNKs can also phosphorylate Bad at serine 128 in vitro and in cultured CGNs and again this promotes the apoptotic effect of Bad. 56 Furthermore, overexpression of the p75NTR in cultured cortical neurons, PC12 cells or glioma cells induces apoptosis associated with JNKdependent phosphorylation of Bad at serine 128.…”

Section: Post-translational Regulation Of Bim and Bad By Phosphorylationmentioning

confidence: 99%

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BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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The molecular mechanisms of neuronal apoptosis have been intensively studied because a considerable amount of apoptosis occurs during the normal development of the mammalian nervous system. This death is important for establishing neuronal populations of the correct size and for ensuring that neurons that contact inappropriate targets are eliminated. 1,2 A second reason for the interest in this area is that there is increasing evidence that apoptosis is one of the mechanisms of neuronal death following acute injuries to the nervous system, such as stroke or traumatic brain injury, and neurons often die by apoptosis in cell culture and animal models of chronic human neurodegenerative disorders. 2 The aim of this article is to review recent work on the function and regulation of the BH3-only subfamily of Bcl-2 proteins in neurons, with an emphasis on studies with sympathetic neurons, cerebellar granule neurons (CGNs) and motoneurons, the best studied in vitro models of neuronal apoptosis, and work that has involved the analysis of neurons from mutant mice.

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Cdc2 Phosphorylation of BAD Links the Cell Cycle to the Cell Death Machinery

Cited by 269 publications

References 46 publications

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Analysis of cyclin B1 and CDK activity during apoptosis induced by camptothecin treatment

BH3-only proteins: key regulators of neuronal apoptosis

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