Olomoucine, an inhibitor of the cdc2/cdk2 kinases activity, blocks plant cells at the G1 to S and G2 to M cell cycle transitions

Glab, Nathalie; Labidi, B.; Qin, Lixian; Tréhin, Christophe; Bergounioux, Catherine; Meijer, Laurent

doi:10.1016/0014-5793(94)01035-8

Cited by 147 publications

(97 citation statements)

References 24 publications

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“…In contrast, Cdk2-speci®c chemical inhibitors, olomoucine and roscovitine (Glab et al, 1994;Vesely et al, 1994;Schulze-Gahmen et al, 1995), decreased cyclin D2-associated kinase activity but had little eect on cyclin D1-associated kinase assays performed in parallel (Figure 2b and c). As expected, the general CDK-inhibitor p21 (WAF1, CIP1, Harper et al, 1993;Xiong et al, 1993) signi®cantly inhibited both cyclin D1-and D2-associated kinase activity (Figure 2b and c).…”

Section: Resultsmentioning

confidence: 96%

“…Several lines of evidence support this conclusion: the Cdk4/Cdk6-speci®c physical inhibitor p16 (Serrano et al, 1993) had little or no eect on the cyclin D2-associated kinase activity while the Cdk2-speci®c chemical inhibitors, roscovitine and olomoucine (Glab et al, 1994;Vesely et al, 1994;Schulze-Gahmen et al, 1995) did block the kinase activity. Finally, cyclin D2 immunocomplexes phosphorylated histone H1 (Figures 2b and 5b), a substrate that is not phosphorylated by Cdk4 or Cdk6 (Matsushime et al, 1994;Meyerson and Harlow, 1994).…”

Section: Discussionmentioning

confidence: 92%

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Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells

et al. 1997

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To investigate the possibility of diering roles for cyclins D1 and D2 in breast epithelial cells, we examined the expression, cell cycle regulation and activity of these two G 1 cyclins in both 184 normal breast epithelial cells and T-47D breast cancer cells. Synchronisation studies in 184 cells demonstrated that cyclin D1 and cyclin D2 were dierentially regulated during G 1 , with cyclin D2 abundance increasing by 3.7-fold but only small changes in cyclin D1 abundance observed. The functional consequences of increased cyclin D2 expression were examined in T-47D cells, which express no detectable cyclin D2. Induced expression of cyclin D2 resulted in increases in cyclin E expression, pRB phosphorylation and the percentage of cells in S-phase, while constitutive expression resulted in a consistent trend toward reduced dependence on serum for continued proliferation. Thus, cyclin D2 is a positive regulator of G 1 progression in breast cells analogous to the well-documented eects of cyclin D1. Indeed, equimolar concentrations of inducible cyclin D1 and D2 resulted in quantitatively similar cell cycle eects. Marked divergence was found, however, in the CDKs activated by the two cyclins in breast epithelial cells. Cyclin D2 complexes contained a higher Cdk2/Cdk4 ratio than cyclin D1 complexes. The cyclin D2-associated kinase activity was largely inhibited by Cdk2-speci®c inhibitors and could phosphorylate histone H1, a substrate for Cdk2 but not for Cdk4 and Cdk6. Therefore, cyclin D2 preferentially activated Cdk2 in breast epithelial cells. In contrast, Cdk4 and Cdk6 were predominantly responsible for cyclin D1-associated kinase activity as previously reported. Thus, although cyclins D1 and D2 elicited similar eects on breast epithelial cell cycle progression they appeared to achieve this end via activation of dierent CDKs. This is the ®rst evidence of cyclin D2 activating Cdk2 in mammalian cells thus providing further evidence that D-type cyclins are not necessarily redundant.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 92%

Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells

et al. 1997

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“…Analysis of CDK2/olomoucine crystals showed that the purine group of olomoucine is located in the pocket where ATP binds to CDK2 [35]. In vivo, olomoucine blocks plant cells at the G1/S and G2/M transitions [36]. Thus, according to this hypothesis, the general structure of the molecule (a specific cytokinin or a synthetic analogue such as olomoucine) may determine its specificity to certain CDK-cyclin complexes, or to other kinases, such as MAP kinases or the kinases that regulate CDK activity.…”

Section: Discussionmentioning

confidence: 99%

Levels of endogenous cytokinins, indole‐3‐acetic acid and abscisic acid during the cell cycle of synchronized tobacco BY‐2 cells

Redig¹,

et al. 1996

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Correlation between cell cycle progression and endogenous levels of plant hormones was studied in synchronized tobacco BY-2 cell suspension cultures. Sixteen different cytokinins, indole-3-acetic acid (IAA) and abscisic acid (ABA) were extracted using solid-phase anion exchange chromatography in combination with immunoaffinity purification, and quantified by mass spectrometry. No significant correlation could be identified for IAA and ABA. In contrast, there were sharp peaks in the levels of specific cytokinins (zeatin-and dihydrozeatin-type) at the end of the S phase and during mitosis. The levels of other cytokinins analyzed, including zeatins N-and O-glucosides, remained low, suggesting that the increased amounts of their corresponding non-glucosylated form resulted from de novo synthesis. These f'mdings suggest that zeatin-and dihydrozeatintype cytokinins might play a specific regulatory role in the progression of the plant cell cycle. One hypothesis to explain cytokinin action is based on a specific interaction with kinases that regulate cell cycle progression, as has been recently shown for the cytokinin analogue olomoucine.

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“…Suspensions of cultured cells of A. thaliana (L.) Heynh. (ecotype Columbia-0) were maintained as described (37). For elicitation, a 7-day-old culture was diluted 10-fold in fresh medium and grown for 16 h. Subsequently, MeJA (Duchefa) at a final concentration of 50 M or an equal volume of solvent (DMSO) was added to the cultures.…”

Section: Methodsmentioning

confidence: 99%