Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex

Abstract

Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes (reaction steps). We have developed a method to: (a) quantify the importance of each of the reaction steps in a kinetic model for the positioning of a switch point [i.e. the restriction point (RP)]; (b) relate this control of reaction steps to their effects on molecular species, using sensitivity and co-control analysis; and thereby (c) go beyond a correlation towards a causal relationship between molecular species and effects. The method is generic and can be applied to responses of any type, but is most useful for the analysis of dynamic and emergent responses such as switch points in the cell cycle. The strength of the analysis is illustrated for an existing mammalian cell cycle model focusing on the RP [Novak B, Tyson J (2004) J Theor Biol 230, 563-579]. The reactions in the model with the highest RP control were those involved in: (a) the interplay between retinoblastoma protein and E2F transcription factor; (b) those synthesizing the delayed response genes and cyclin D/Cdk4 in response to growth signals; (c) the E2F-dependent cyclin E/Cdk2 synthesis reaction; as well as (d) p27 formation reactions. Nine of the 23 intermediates were shown to have a good correlation between their concentration control and RP control. Sensitivity and co-control analysis indicated that the strongest control of the RP is mediated via the cyclin E/Cdk2:p27 complex concentration. Any perturbation of the RP could be related to a change in the concentration of this complex; apparent effects of other molecular species were indirect and always worked through cyclin E/Cdk2:p27, indicating a causal relationship between this complex and the positioning of the RP. Abbreviations DRG, delayed response genes; ERG, early response genes; MCA, metabolic control analysis; Rb, retinoblastoma protein; RP, restriction point.

Regulation of p27Kip1by mitogen-induced tyrosine phosphorylation

“…p27 level have been proposed as prognostic and therapeutic marker in many different human malignancies. 5 The increased mechanistic knowledge on its regulation revealed that additional determination of its localization is of prognostic value. 5 Future studies should reveal if the determination of p27 tyrosine phosphorylation could improve its potential value to serve as prognostic and/or therapeutic marker in human hyperproliferative disorders.…”

“…3 Controlling Cdk kinase activities, p27 level, localization and activity in mid-G 1 phase can directly influence passage through the restriction point. 4,5 Multiple mitogenic and antiproliferative signal transduction pathways can regulate p27 synthesis, stability, localization or activity. As they converge at the level of p27 regulation, this may serve as a platform to process and integrate diverse mitogenic and antimitogenic signals.…”

Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering

“…Indeed, MCA has been extended [67,[105][106][107] and applied to periodic phenomena such as glycolytic oscillations [108,109] and the cell cycle [110], to transient phenomena such as transient phosphorylation of signaltransduction proteins [111] and even to bistability [112]. It is especially interesting to consider such dynamic generalizations in a control systems context [113,114].…”

Antiprogestins in Ovarian Cancer

“…The growth inhibitory effect of mifepristone on ovarian cancer cells is associated with inhibition of DNA synthesis, down-regulation of the transcription factor E2F1 needed for S phase progression, and inhibition of the activity of Cdk-2. This cell cycle regulatory protein is critical to promote the transition of cells in the cell cycle from G1 to S phase (Conradie et al,2010). For instance, the activity of Cdk-2 is needed for the stimulation of histone gene transcription (Zhao et al,2000), which is one of the major events marking the entry into the S phase.…”

“…For instance, the activity of Cdk-2 is needed for the stimulation of histone gene transcription (Zhao et al,2000), which is one of the major events marking the entry into the S phase. To drive cell cycle progression, Cdk-2 should be free of p21 cip1 and p27 kip1 binding (Conradie et al,2010), bound to cyclin E, and allocated to the nucleus to phosphorylate cell cycle regulatory proteins (Brown et al,2004;Lents et al,2002). Mifepristone, ORG-31710 and CDB-2914 affect the nucleocytoplasmic trafficking of Cdk inhibitors p21 cip1 and p27 kip1 , Cdk-2 and its co-factor cyclin E. The antiprogestins also increase p21 cip1 and p27 kip1 abundances in both cytoplasm and nuclear compartments in correlation with decreased Cdk-2 and cyclin E nuclear levels, increased cytoplasmic cyclin E, and a remarkable decline in the activity of Cdk-2 in both subcellular compartments (Goyeneche et al,2007;Goyeneche et al,2011).…”