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      HDAC Inhibitors Disrupt Programmed Resistance to Apoptosis During Drosophila Development

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          Abstract

          We have previously shown that the ability to respond to apoptotic triggers is regulated during Drosophila development, effectively dividing the fly life cycle into stages that are either sensitive or resistant to apoptosis. Here, we show that the developmentally programmed resistance to apoptosis involves transcriptional repression of critical proapoptotic genes by histone deacetylases (HDACs). Administration of HDAC inhibitors (HDACi), like trichostatin A or suberoylanilide hydroxamic acid, increases expression of proapoptotic genes and is sufficient to sensitize otherwise resistant stages. Conversely, reducing levels of proapoptotic genes confers resistance to otherwise sensitive stages. Given that resistance to apoptosis is a hallmark of cancer cells, and that HDACi have been recently added to the repertoire of FDA-approved agents for cancer therapy, our results provide new insights for how HDACi help kill malignant cells and also raise concerns for their potential unintended effects on healthy cells.

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          Most cited references 39

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            The hallmarks of cancer.

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              Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR.

               M. Pfaffl (2002)
              Real-time reverse transcription followed by polymerase chain reaction (RT-PCR) is the most suitable method for the detection and quantification of mRNA. It offers high sensitivity, good reproducibility and a wide quantification range. Today, relative expression is increasingly used, where the expression of a target gene is standardised by a non-regulated reference gene. Several mathematical algorithms have been developed to compute an expression ratio, based on real-time PCR efficiency and the crossing point deviation of an unknown sample versus a control. But all published equations and available models for the calculation of relative expression ratio allow only for the determination of a single transcription difference between one control and one sample. Therefore a new software tool was established, named REST (relative expression software tool), which compares two groups, with up to 16 data points in a sample and 16 in a control group, for reference and up to four target genes. The mathematical model used is based on the PCR efficiencies and the mean crossing point deviation between the sample and control group. Subsequently, the expression ratio results of the four investigated transcripts are tested for significance by a randomisation test. Herein, development and application of REST is explained and the usefulness of relative expression in real-time PCR using REST is discussed. The latest software version of REST and examples for the correct use can be downloaded at http://www.wzw.tum.de/gene-quantification/.
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                Author and article information

                Journal
                G3 (Bethesda)
                Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                2160-1836
                27 April 2017
                June 2017
                : 7
                : 6
                : 1985-1993
                Affiliations
                [* ]Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Wisconsin 53705-2222
                []Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Wisconsin 53705-2222
                Author notes
                [1]

                These authors contributed equally to this work.

                [2]

                Present address: Vollum Institute, Oregon Health & Sciences University, Portland, OR 97239.

                [3]

                Present address: Developmental, Regenerative, and Stem Cell Program, Washington University in St. Louis, MO 63130.

                [4 ]Corresponding author: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222. E-mail: bashirullah@ 123456wisc.edu
                Article
                GGG_041541
                10.1534/g3.117.041541
                5473774
                28455414
                Copyright © 2017 Kang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 39, Pages: 9
                Product
                Categories
                Investigations

                Genetics

                hdac1/rpd3, saha, tsa, caspase activation, apoptotic thresholds

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