Author: Axel H. Schönthal Publisher: Springer Science & Business Media ISBN: 1592598110 Category : Medical Languages : en Pages : 362
Book Description
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 enforced—for 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.
Author: Zahid H. Siddik Publisher: Springer Science & Business Media ISBN: 1607611783 Category : Medical Languages : en Pages : 276
Book Description
Much work over the last two decades has firmly established that loss of cell cycle checkpoint regulation, and resultant unabated cellular proliferation, is an inherent characteristic of cancer. This loss may occur through aberration in any single component involved in signal transduction pathways that orchestrate checkpoint regulation, which may manifest through either a failure to activate the checkpoint or a failure to respond to the activated checkpoint. In normal cells, checkpoint pathways are activated when genetic or cellular homeostasis is compromised, and signals are then transduced to re-stabilize homeostasis, and, failing this, to activate the apoptotic machinery to induce a cellular suicidal response. This implies that both survival and cell death pathways are induced following checkpoint activation, and that the final decision is dependant on the net result of integrating the two sets of signals. It is intriguing that checkpoint pathways are also critical in cancer therapy to provide an apoptotic stimulus when cellular damage induced by the therapeutic agent is detected by the sensor system. Therefore, it is not surprising that failure in pro-survival checkpoint response will render tumor cells hypersensitive to cytotoxics and, conversely, failure in pro-apoptotic checkpoint response will induce genetic instability and/or therapeutic resistance. Understanding the intricacies of checkpoint response is, therefore, central to the design of therapeutic regimen that will enhance antitumor effects. Although early versions of this design entail combination of cytotoxic agents with cell cycle or checkpoint inhibitors, a greater understanding of the concepts could make such combinations clinically more effective. The contributions in this book will consolidate the current state of knowledge on checkpoint responses that may lay the foundation for hypothesis-driven rational approaches in advancing the management of cancer. The immediate attraction of the book to the scientific community is that it represents a timely opportunity to build upon existing concepts of checkpoints to expand our understanding of the inner workings of the critical checkpoint machinery. The present understanding has provided ample appreciation that response to checkpoint activation is manifested through coordinated inhibition of cyclin-dependent kinase (CDK) complexes in G1, S and/or the G2 phase in order to arrest the cell cycle. Kinase inhibition can occur through several mechanisms, including inhibitory phosphorylation of CDK, destruction of the cognate cyclins, and recruitment of CDK inhibitors from the INK and WAF1/CIP1 families. However, the wealth of information from recent discoveries needs to be examined critically to consolidate our conceptual knowledge of checkpoints. At the same time, there is acute awareness in the diversity of checkpoint response between cytotoxic agents, and this serves as a reminder of the magnitude of complexity that is inherent in checkpoint regulation. This volume is intended to bring the cancer research community closer toward an improved understanding of this regulation, how checkpoint abnormalities can impact negatively on cancer therapy, and emerging strategies to target checkpoint response as a therapeutic end-point.
Author: Axel H. Schönthal Publisher: Springer Science & Business Media ISBN: 1592597882 Category : Medical Languages : en Pages : 328
Book Description
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 enforced—for 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.
Author: Howard B. Lieberman Publisher: Springer Science & Business Media ISBN: 1592596460 Category : Science Languages : en Pages : 366
Book Description
The field of cell cycle regulation is based on the observation that the life cycle of a cell progresses through several distinct phases, G1, M, S, and G2, occurring in a well-defined temporal order. Details of the mechanisms involved are rapidly emerging and appear extraordinarily complex. Furthermore, not only is the order of the phases important, but in normal eukaryotic cells one phase will not begin unless the prior phase is completed successfully. Che- point control mechanisms are essentially surveillance systems that monitor the events in each phase, and assure that the cell does not progress prematurely to the next phase. If conditions are such that the cell is not ready to progress—for example, because of incomplete DNA replication in S or DNA damage that may interfere with chromosome segregation in M—a transient delay in cell cycle progression will occur. Once the inducing event is properly handled— for example, DNA replication is no longer blocked or damaged DNA is repaired—cell cycle progression continues. Checkpoint controls have recently been the focus of intense study by investigators interested in mechanisms that regulate the cell cycle. Furthermore, the relationship between checkpoint c- trol and carcinogenesis has additionally enhanced interest in these cell cycle regulatory pathways. It is clear that cancer cells often lack these checkpoints and exhibit genomic instability as a result. Moreover, several tumor suppressor genes participate in checkpoint control, and alterations in these genes are as- ciated with genomic instability as well as the development of cancer.
Author: Wei Dai Publisher: Springer Science & Business Media ISBN: 1597452742 Category : Medical Languages : en Pages : 320
Book Description
Extensive research has uncovered a set of molecular surveillance mechanisms – commonly called “checkpoints” – which tightly monitor cell-cycle processes. Today’s anticancer drug development has identified many of these cell-cycle checkpoint molecules as effective targets. Research now promises to uncover a new generation of anticancer drugs with improved therapeutic indices based on their ability to target emerging checkpoint components. Checkpoint Responses in Cancer Therapy summarizes the advances made over the past 20 years, identifying components of cell-cycle checkpoints and their molecular regulation during checkpoint activation and validating the use of checkpoint proteins as targets for the development of anticancer drugs. This book’s distinguished panel of authors takes a close look at topics ranging from the major molecular players affecting DNA synthesis and the response to DNA damage to advances made in the identification of chemical compounds capable of inhibiting individual mitotic kinases. Illuminating and authoritative, Checkpoint Responses in Cancer Therapy offers a critical summary of findings for researchers in the pharmaceutical and biotechnology industries and a valuable resource for academic scientists in cancer research and the study of cell-cycle regulation, signal transduction and apoptosis.
Author: Axel H. Schönthal
Author: Zahid H. Siddik
Author: Axel H. Schönthal
Author: Axel H. Schönthal
Author: Howard B. Lieberman
Author: Axel H. Schönthal
Author: Wei Dai
Author: 
Author: Bruce Alberts
Author: Michael B. Kastan