Checkpoint Controls and Cancer

Intracellular checkpoint controls constitute a network of signal transd- tion pathways that protect cells from external stresses and internal errors. Ext- nal stresses can be generated by the continuous assault of DNA-damaging agents, such as environmental mutagens, ultraviolet (UV) light, ionizing radiation, or the reactive oxygen species that can arise during normal cellular metabolism. In response to any of these assaults on the integrity of the genome, the activation of the network of checkpoint control pathways can lead to diverse cellular responses, such as cell cycle arrest, DNA repair, or elimination of the cell by cell death (apoptosis) if the damage cannot be repaired. Moreover, internal errors can occur during the highly orchestrated replication of the cellular genome and its distribution into daughter cells. Here, the temporal order of these cell cycle events must be strictly enforcedfor example, to ensure that DNA replication is c- plete and occurs only once before cell division, or to monitor mitotic spindle assembly, and to prevent exit from mitosis until chromosome segregation has been completed. Thus, well functioning checkpoint mechanisms are central to the maintenance of genomic integrity and the basic viability of cells and, the- fore, are essential for proper development and survival. The importance of proper functioning of checkpoints becomes plainly obvious under conditions in which this control network malfunctions and fails. Depending on the severity and timing, failure of this machinery can lead to embryonic lethality, genetic diseases, and cancer.

Includes supplementary material: sn.pub/extras

Klappentext
Intracellular checkpoint controls constitute a network of signal transduction pathways that protect cells from external stresses and internal errors by means of cell cycle arrest, DNA repair, or apoptosis. Failure of this machinery can lead to embryonic death, genetic diseases, and cancer. In Checkpoint Controls and Cancer, Volume 1: Reviews and Model Systems, Axel H. Schönthal, PhD, marshals a prestigious panel of researchers working at the cutting edges of their fields to comprehensively review the complexities of checkpoint controls and the model systems available to study them. The authors introduce all of the important components of checkpoint controls, describe their intricate interactions, and highlight the relevance of these processes to the cancer problem. Additional chapters illustrate the advantages of using such diverse model systems as intact human skin, knockout mice, Xenopus, and yeast, and show how they can cross-fertilize and accelerate research both across disciplines and beyond the boundaries of a particular species. A second volume, Activation and Regulation Protocols, provides readily reproducible experimental protocols for studying the molecular components of checkpoint controls and their regulation.
Comprehensive and up-to-date, the two volumes of Checkpoint Controls and Cancer offer novice and experienced researchers alike not only entré into the complexities of this vast field, but also to the full panoply of productive tools needed to deepen understanding of the systems, as well as to develop new and more effective cancer therapies.

Inhalt
Reviews of Checkpoint Controls, Their Involvement in the Development of Cancer, and Approaches to Their Investigation.- G1 and S-Phase Checkpoints, Chromosome Instability, and Cancer.- Analyzing the G2/M Checkpoint.- Analyzing the Spindle Checkpoint in Yeast and Frogs.- Cell Cycle Checkpoint Control Mechanisms That Can Be Disrupted in Cancer.- Analyzing Checkpoint Controls in Diverse Model Systems.- Establishment of a Cell-Free System to Study the Activation of Chk2.- Analyzing Checkpoint Controls in Human Skin.- Generation and Analysis of Brca1 Conditional Knockout Mice.- Analysis of Cell Cycle Progression and Genomic Integrity in Early Lethal Knockouts.- Xenopus Cell-Free Extracts to Study the DNA Damage Response.- A Xenopus Cell-Free System for Functional Analysis of the Chfr Ubiquitin Ligase Involved in Control of Mitotic Entry.- Control of Mitotic Entry After DNA Damage in Drosophila.- Methods for Analyzing Checkpoint Responses in Caenorhabditis elegans.- Assaying the Spindle Checkpoint in the Budding Yeast Saccharomyces cerevisiae.- Purification and Analysis of Checkpoint Protein Complexes From Saccharomyces cerevisiae.