Control of timing of embryonic M-phase entry and exit is differentially sensitive to CDK1 and PP2A balance

Dika, Mohammed El; Dudka, Damian; Prigent, Claude; Tassan, Jean Pierre; Kloc, Małgorzata; Kubiak, Jacek Z.

doi:10.1387/ijdb.140101jk

Cited by 6 publications

(6 citation statements)

References 30 publications

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“…In reality, this time point is determined by the minimal level of CDK1 activation that is sufficient to trigger significant phosphorylation of its critical substrates. The accumulation of substrates phosphorylated by CDK1 and dephosphorylated by PP2A is escalating and dynamic; thus, even in biological experiments, we have to arbitrarily choose the time point of the M-phase entry (El Dika et al, 2014b). The simulations presented in this paper show how inhibitors of CDK1 and PP2A (RO3306 and OA respectively) modify the curves and in consequence the timing of M-phase entry in all experimental variants, i.e.…”

Section: Discussionmentioning

confidence: 95%

“…We do not take into account the complex regulation via Greatwall kinase and PP1. tion of its substrates CDC27 and MCM4 (El Dika et al, 2014b). Conversely, inhibition of PP2A phosphatase by okadaic acid (OA; at 1 or 2.5 mM concentration, but not at 200 nM or lower) accelerates the onset of mitosis also in a dose-dependent manner (Fig.…”

Section: Interplay Between Cdk1 and Pp2a Modifies Timing Of M-phase Ementioning

confidence: 94%

“…Conversely, inhibition of PP2A phosphatase by okadaic acid (OA; at 1 or 2.5 mM concentration, but not at 200 nM or lower) accelerates the onset of mitosis also in a dose-dependent manner (Fig. 2;Felix et al, 1989;El Dika et al, 2014b).…”

Section: Interplay Between Cdk1 and Pp2a Modifies Timing Of M-phase Ementioning

confidence: 99%

“…The process of CDK1 activation is also slowed down, independently of the CDC25/Myt1/Wee1 loop, by a CDC6-dependent inhibitory mechanism inhibiting CDK1 (El Dika et al, 2014a). Finally, the levels of CDK1-phosphorylated substrates, which effectively induce M-phase entry, can be counterbalanced to different extent by the PP2A phosphatase (El Dika et al, 2014b). Any alteration of these elements of the controlling network immediately provokes a compensatory response from another element(s) restoring the equilibrium.…”

Section: Introductionmentioning

confidence: 99%

“…However, in Xenopus laevis embryo cell-free extracts, moderate modifications of CDK1 and PP2A activities change the timing of M-phase entry. This indicates that Xenopus early embryo contains a specific mechanism allowing for fine control of cleavages (El Dika et al, 2014b), which may be important for temporal adjustment of cell divisions in the overall developmental program.…”

Section: Introductionmentioning

confidence: 99%

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Flexibility vs. robustness in cell cycle regulation of timing of M-phase entry in Xenopus laevis embryo cell-free extract

Dȩbowski¹,

Dika²,

Malejczyk³

et al. 2016

Int. J. Dev. Biol.

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International audienceDuring the cell cycle, cyclin dependent kinase 1 (CDK1) and protein phosphatase 2A (PP2A) play major roles in the regulation of mitosis. CDK1 phosphorylates a series of substrates triggering M-phase entry. Most of these substrates are dephosphorylated by PP2A. To allow phosphorylation of CDK1 substrates, PP2A is progressively inactivated upon M-phase entry. We have shown previously that the interplay between these two activities determines the timing of M-phase entry. Slight diminution of CDK1 activity by the RO3306 inhibitor delays M-phase entry in a dose-dependent manner in Xenopus embryo cell-free extract, while reduction of PP2A activity by OA inhibitor accelerates this process also in a dose-dependent manner. However, when a mixture of RO3306 and OA is added to the extract, an intermediate timing of M-phase entry is observed. Here we use a mathematical model to describe and understand this interplay. Simulations showing acceleration and delay in M-phase entry match previously described experimental data. CDC25 phosphatase is a major activator of CDK1 and acts through CDK1 Tyr15 and Thr14 dephosphorylation. Addition of CDC25 activity to our mathematical model was also consistent with our experimental results. To verify whether our assumption that the dynamics of CDC25 activation used in this model are the same in all experimental variants, we analyzed the dynamics of CDC25 phosphorylation, which reflect its activation. We confirm that these dynamics are indeed very similar in control extracts and when RO3306 and OA are present separately. However, when RO3306 and OA are added simultaneously to the extract, activation of CDC25 is slightly delayed. Integration of this parameter allowed us to improve our model. Furthermore, the pattern of CDK1 dephosphorylation on Tyr15 showed that the real dynamics of CDK1 activation are very similar in all experimental variants. The model presented here accurately describes, in mathematical terms, how the interplay between CDK1, PP2A and CDC25 controls the flexible timing of M-phase entry

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Section: Discussionmentioning

confidence: 95%

Section: Interplay Between Cdk1 and Pp2a Modifies Timing Of M-phase Ementioning

confidence: 94%

Section: Interplay Between Cdk1 and Pp2a Modifies Timing Of M-phase Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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