Release from cell cycle arrest with Cdk4/6 inhibitors generates highly synchronised cell cycle progression in human cell culture (original) (raw)
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In Vivo, 2005
Malignant neoplasms consist of heterogeneous cell populations and their cellular elements proliferate asynchronously. Since the tumor cells of various cell cycle phases respond differently to many chemotherapeutic drugs, attempts at synchronization seemed to be a promising way to achieve a more powerful antineoplastic effect. Mainly based on in vitro data, it was shown that numerous compounds, including hormones, were able to arrest the cell cycle in different phases, and some of them also induced apoptotic cell death. The better understanding of the molecular mechanisms of cell cycle control has brought the cyclin-dependent kinases into focus and hundreds of compounds have been synthesized in order to regulate malignant cells at their checkpoints, especially at G1 progression. Some of these compounds have been found to be effective not only in vitro, but also in in vivo experiments, and they were further evaluated in Phase I-II clinical trials. Generally speaking, these studies have yielded modest, although potentially promising, results, but the adverse effects sometimes restricted the applicability of the products. Nevertheless, extended studies in cancer patients are under way. Moreover, after encouraging preclinical investigations, the combination of cell cycle regulators with different cytostatic drugs may offer a novel therapeutic alternative in the field of oncology.
Cell-cycle inhibitors: three families united by a common cause
Gene, 2000
In the cellular program leading to DNA synthesis, signals that drive cells into S-phase converge at the level of CDK activity. The products of at least three different gene families, Ink4, Cip/Kip and the pRb pocket-protein family, suppress S-phase entry. Ink4 proteins act by antagonizing the formation and activation of cyclin D-CDK4 complexes, of which the ultimate downstream target as related to S-phase entry appears to be pRb. Cip/Kip inhibitors impinge upon that pathway by inhibiting CDK2 kinases that participate in the inactivation of pRb and, like cyclin E, may also have roles independent of pRb. How the activities of these three classes of proteins are coordinated remains obscure. In recent years, development of mouse models has accelerated the elucidation of this complex network, showing roles that are sometimes cooperative and sometimes overlapping. We will discuss the interrelationships between Cip/Kip inhibitors and the components of the pRb pathway, and how their activities ultimately regulate cell proliferation.
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Deregulation of the G1-S transition of the cell cycle is a common feature of human cancer. Tumor-associated alter- ations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27Kip1), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development.
Distinct mechanisms act in concert to mediate cell cycle arrest
Proceedings of the National Academy of Sciences, 2009
In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.
The dynamics of cell cycle regulation
BioEssays, 2002
Major events of the cell cycle-DNA synthesis, mitosis and cell division-are regulated by a complex network of protein interactions that control the activities of cyclin-dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological properties of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast.
Biophysical Journal, 2013
The eukaryotic cell cycle is characterized by alternating oscillations in t he activities of cycli n-dependent kinase (Cdk) and the anaphase-promoting complex (APC). Successful completion of the cell cycle is dependent on the precise, temporally ordered appearance of these activities. A modest level of Cdk activity is sufficient to initiate DNA replication , b ut mitosis and APC activation require an elevated Cdk activity. In present-day eukaryotes, this temporal o rder is prov ided by a complex network of regulatory proteins that control both Cdk and APC activities via sharp thresholds, bistability, and time delays. Using simple computational models, we show here that these dynamical features of cell-cycle organization could emerge in a control system driven by a single Cdk/cyclin complex and APC wired in a negative-feedback loop. We show that ordered phosphorylation of cellular proteins could be explained by multisite phosphorylation/dephosphorylation and competition of substrates for interconverting kinase (Cdk) and phosphatase. In addition, the competition of APC substrates fo r ubiquitylation can create and maintain sustained oscillations in cyclin levels. We propose a sequence of models that gets closer and closer to a realistic model of cell-cycle control in yeast. Since these models lack the elaborate control mechanisms characteristic of modern eukaryotes, they suggest that bistability and time delay may have characterized eukaryotic cell divisions before the current cell-cycle control network evolved in all its complexity.