Dataset Information

Ciliberto2003 - CyclinE / Cdk2 timer in the cell cycle of Xenopus laevis embryo

ABSTRACT: Ciliberto2003 - CyclinE / Cdk2 timer in the cell cycle of Xenopus laevis embryo This model is described in the article: A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus laevis embryos. Ciliberto A, Petrus MJ, Tyson JJ, Sible JC. Biophys. Chem. 2003 Jul; 104(3): 573-589 Abstract: Early cell cycles of Xenopus laevis embryos are characterized by rapid oscillations in the activity of two cyclin-dependent kinases. Cdk1 activity peaks at mitosis, driven by periodic degradation of cyclins A and B. In contrast, Cdk2 activity oscillates twice per cell cycle, despite a constant level of its partner, cyclin E. Cyclin E degrades at a fixed time after fertilization, normally corresponding to the midblastula transition. Based on published data and new experiments, we constructed a mathematical model in which: (1) oscillations in Cdk2 activity depend upon changes in phosphorylation, (2) Cdk2 participates in a negative feedback loop with the inhibitory kinase Wee1; (3) cyclin E is cooperatively removed from the oscillatory system; and (4) removed cyclin E is degraded by a pathway activated by cyclin E/Cdk2 itself. The model's predictions about embryos injected with Xic1, a stoichiometric inhibitor of cyclin E/Cdk2, were experimentally validated. This model is hosted on BioModels Database and identified by: BIOMD0000000697. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: BIOMD0000000697 | BioModels | 2018-04-23

REPOSITORIES: BioModels

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A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus laevis embryos.

Ciliberto Andrea A Petrus Matthew J MJ Tyson John J JJ Sible Jill C JC

Biophysical chemistry 20030701 3

Early cell cycles of Xenopus laevis embryos are characterized by rapid oscillations in the activity of two cyclin-dependent kinases. Cdk1 activity peaks at mitosis, driven by periodic degradation of cyclins A and B. In contrast, Cdk2 activity oscillates twice per cell cycle, despite a constant level of its partner, cyclin E. Cyclin E degrades at a fixed time after fertilization, normally corresponding to the midblastula transition. Based on published data and new experiments, we constructed a ma ...[more]

PMID: 12914904

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Project description:Novak1993 - Cell cycle M-phase control The model reproduces Figure 9 of the paper. Please note that active MPF and cyclin concentrations in the paper are given relative to total cdc2 concentration (100nM). Active MPF (dimer_p) is the cyclin-cdc2 complex that is phosphorylated at Thr161. The earlier versions of the model was successfully tested on MathSBML and Jarnac, and the current version was checked in Copasi. This model is described in the article: Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos. Novak B, Tyson JJ. J. Cell. Sci. 1993 Dec; 106 ( Pt 4): 1153-1168 Abstract: To contribute to a deeper understanding of M-phase control in eukaryotic cells, we have constructed a model based on the biochemistry of M-phase promoting factor (MPF) in Xenopus oocyte extracts, where there is evidence for two positive feedback loops (MPF stimulates its own production by activating Cdc25 and inhibiting Wee1) and a negative feedback loop (MPF stimulates its own destruction by indirectly activating the ubiquitin pathway that degrades its cyclin subunit). To uncover the full dynamical possibilities of the control system, we translate the regulatory network into a set of differential equations and study these equations by graphical techniques and computer simulation. The positive feedback loops in the model account for thresholds and time lags in cyclin-induced and MPF-induced activation of MPF, and the model can be fitted quantitatively to these experimental observations. The negative feedback loop is consistent with observed time lags in MPF-induced cyclin degradation. Furthermore, our model indicates that there are two possible mechanisms for autonomous oscillations. One is driven by the positive feedback loops, resulting in phosphorylation and abrupt dephosphorylation of the Cdc2 subunit at an inhibitory tyrosine residue. These oscillations are typical of oocyte extracts. The other type is driven by the negative feedback loop, involving rapid cyclin turnover and negligible phosphorylation of the tyrosine residue of Cdc2. The early mitotic cycles of intact embryos exhibit such characteristics. In addition, by assuming that unreplicated DNA interferes with M-phase initiation by activating the phosphatases that oppose MPF in the positive feedback loops, we can simulate the effect of addition of sperm nuclei to oocyte extracts, and the lengthening of cycle times at the mid-blastula transition of intact embryos. This model is hosted on BioModels Database and identified by: BIOMD0000000107. To cite BioModels Database, please use: BioModels: ten-year anniversary . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in the ADPKD genes PKD1 and PKD2 account for nearly all the cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1, the product of PKD1, regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can acts as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2. In this study we utilized different kidney cell lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation. Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 activity and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of STAT-1/p21 pathway. Genome-wide expression analysis in these cells revealed that expression of the cyclin-dependent kinase inhibitor, p57 is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels. Our results indicate the probable involvement of p57 on epithelial cell proliferation in polycystic kidney disease. In addition, it confirms that PKD2-induced proliferation is a multifactorial process. We used microarrays to study the modulation of gene expression by mutated PKD2 in the primary tubular epithelial cells of a transgenic rat mode Keywords: transgene Gene expression in the primary tubular epithelial of a transgenic rat mode with mutated PKD2 was compared with that of SD control rats

Dataset Information

Ciliberto2003 - CyclinE / Cdk2 timer in the cell cycle of Xenopus laevis embryo

Publications

A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus laevis embryos.

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