Milestones in cell division To cycle or not to cycle: a critical decision in cancer (original) (raw)

Mammalian Cells Cycle without the D-Type Cyclin-Dependent Kinases Cdk4 and Cdk6

Cell, 2004

highlighted by the fact that pRb can bind more than 120 and Mariano Barbacid 1, * cellular proteins (Morris and Dyson, 2001). 1 Molecular Oncology Program Phosphorylation of pRb by D-type cyclin/Cdk4 or Centro Nacional de Investigaciones Oncoló gicas (CNIO) Cdk6 complexes results in its partial inactivation, which E-28029 Madrid in turn allows expression of a limited number of tran-Spain scriptional targets needed to drive cells through the G1 2 EA2406 University of Bordeaux 2 phase of the cell cycle. For instance, some of these F-33076 Bordeaux targets are additional cyclins, such as the E-type cyclins France (E1 and E2), whose primary role is to activate Cdk2. Active E-type cyclin/Cdk2 complexes further phosphorylate pRb (Lundberg and Weinberg, 1998; Harbour et Summary al., 1999) leading to a wave of transcriptional activity essential to proceed through the G1/S transition. How-Cdk4 and Cdk6 are thought to be essential for initiation ever, recent genetic evidence indicating that Cdk2 and of the cell cycle in response to mitogenic stimuli. Previ-E-type cyclins are not required for mitotic cell division ous studies have shown that Cdk4 is dispensable for has challenged this model (Berthet et al., 2003; Ortega et proliferation in most cell types, an observation attribal., 2003; Geng et al., 2003; Parisi et al., 2003)

CDKs: Much More Than Just the Control of Cell Cycle Progression

Journal of Cell Science & Therapy, 2014

Lee and colleagues have shown that CDK4 plays a central role in glucose homeostasis. Insulin activates cyclin D1-CDK4, leading to a decrease in circulating glucose as a consequence of the down-regulation of main genes involved in liver gluconeogenesis. Commentary In recent years, our knowledge of CDK regulation has improved significantly and is no longer restricted to just its role in the control of cell cycle progression. Cyclin-dependent kinases (CDKs) are serine/ threonine protein kinases that are associated with their specific partners, cyclins which phosphorylate their protein targets. Thus, the cyclin-CDK complex works as a holoenzyme. The control of cell cycle progression by cyclin-CDK complexes was first studied several years ago, in the context of high proliferation rates and cancer. Understanding how CDKs function was one of the main aims of these studies, as the loss of this regulation can alter cell proliferation rates which, in the worst case scenario, may translate into malignant tumours.

Cdk1 is sufficient to drive the mammalian cell cycle

Nature, 2007

Unicellular organisms such as yeasts require a single cyclindependent kinase, Cdk1, to drive cell division 1 . In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis 2 . This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks 3-8 . Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks 8-10 . Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins 11-14 . Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.

Selective chemical inhibition as a tool to study Cdk1 and Cdk2 functions in the cell cycle

Cell Cycle, 2008

Cyclin-dependent kinases are highly conserved among all eukaryotes, and have essential roles in the cell cycle. However, these roles are still only poorly understood at a molecular level, partly due to the functional redundancy of different Cdk complexes. Indeed, mice knockouts have even thrown into some doubt the assumed essential roles for Cdk2-cyclin E in triggering S-phase, but this is almost certainly due to compensation by Cdk1 complexes. By combining both knockout approaches and chemical Cdk inhibition in Xenopus egg extracts, we have shown that one reason for functional redundancy of Cdk control of S-phase is that Cdk activity required to trigger S-phase is very low. Cdk1 contributes to this activity even in the presence of Cdk2, and Cdk activity at this stage does not show "switch-like" regulation, as at the onset of mitosis. It is important to try to confirm and extend these findings to other cell-types, and to explain why different cells might have evolved different requirements for Cdk activity. In this paper, we present data that suggest that selective chemical Cdk inhibition will be a useful tool towards achieving this goal. † These authors contirbuted equally to this work.

Regulation of the cell cycle the cdk2 protein kinase in cultured human fibroblasts

The Journal of Cell Biology

In mammalian cells inhibition of the cdc2 function results in arrest in the G2-phase of the cell cycle. Several cdc2-related gene products have been identified recently and it has been hypothesized that they control earlier cell cycle events. Here we have studied the relationship between activation of one of these cdc2 homologs, the cdk2 protein kinase, and the progression through the cell cycle in cultured human fibroblasts. We found that cdk2 was activated and spe-cifically localized to the nucleus during S phase and G2. Microinjection of afffinity-purified anti-cdk2 antibodies but not of affinity-purified anti-cdc2 antibodies, during G1, inhibited entry into S phase. The specificity of these effects was demonstrated by the fact that a plasmid-driven cdk2 overexpression counteracted the inhibition. These results demonstrate that the cdk2 protein kinase is involved in the activation of DNA synthesis.