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      Centrosome-associated regulators of the G 2/M checkpoint as targets for cancer therapy

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          Abstract

          In eukaryotic cells, control mechanisms have developed that restrain cell-cycle transitions in response to stress. These regulatory pathways are termed cell-cycle checkpoints. The G 2/M checkpoint prevents cells from entering mitosis when DNA is damaged in order to afford these cells an opportunity to repair the damaged DNA before propagating genetic defects to the daughter cells. If the damage is irreparable, checkpoint signaling might activate pathways that lead to apoptosis. Since alteration of cell-cycle control is a hallmark of tumorigenesis, cell-cycle regulators represent potential targets for therapy. The centrosome has recently come into focus as a critical cellular organelle that integrates G 2/M checkpoint control and repairs signals in response to DNA damage. A growing number of G 2/M checkpoint regulators have been found in the centrosome, suggesting that centrosome has an important role in G 2/M checkpoint function. In this review, we discuss centrosome-associated regulators of the G 2/M checkpoint, the dysregulation of this checkpoint in cancer, and potential candidate targets for cancer therapy.

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          Most cited references174

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          CDK inhibitors: positive and negative regulators of G1-phase progression.

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            p53 mutations in human cancers.

            Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
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              Ubiquitin ligases: cell-cycle control and cancer.

              A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1-CUL1-F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
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                Author and article information

                Journal
                Mol Cancer
                Molecular Cancer
                BioMed Central
                1476-4598
                2009
                13 February 2009
                : 8
                : 8
                Affiliations
                [1 ]Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, PR China
                [2 ]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
                Article
                1476-4598-8-8
                10.1186/1476-4598-8-8
                2657106
                19216791
                fc397a64-96ae-4b25-bee4-6f2b56158e02
                Copyright © 2009 Wang et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 October 2008
                : 13 February 2009
                Categories
                Review

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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