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      A Retinoblastoma Orthologue Is a Major Regulator of S-Phase, Mitotic, and Developmental Gene Expression in Dictyostelium

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          Abstract

          Background

          The retinoblastoma tumour suppressor, Rb, has two major functions. First, it represses genes whose products are required for S-phase entry and progression thus stabilizing cells in G1. Second, Rb interacts with factors that induce cell-cycle exit and terminal differentiation. Dictyostelium lacks a G1 phase in its cell cycle but it has a retinoblastoma orthologue, rblA.

          Methodology/Principal Findings

          Using microarray analysis and mRNA-Seq transcriptional profiling, we show that RblA strongly represses genes whose products are involved in S phase and mitosis. Both S-phase and mitotic genes are upregulated at a single point in late G2 and again in mid-development, near the time when cell cycling is reactivated. RblA also activates a set of genes unique to slime moulds that function in terminal differentiation.

          Conclusions

          Like its mammalian counterpart Dictyostelium, RblA plays a dual role, regulating cell-cycle progression and transcriptional events leading to terminal differentiation. In the absence of a G1 phase, however, RblA functions in late G2 controlling the expression of both S-phase and mitotic genes.

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          Most cited references54

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

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            The Amphimedon queenslandica genome and the evolution of animal complexity.

            Sponges are an ancient group of animals that diverged from other metazoans over 600 million years ago. Here we present the draft genome sequence of Amphimedon queenslandica, a demosponge from the Great Barrier Reef, and show that it is remarkably similar to other animal genomes in content, structure and organization. Comparative analysis enabled by the sequencing of the sponge genome reveals genomic events linked to the origin and early evolution of animals, including the appearance, expansion and diversification of pan-metazoan transcription factor, signalling pathway and structural genes. This diverse 'toolkit' of genes correlates with critical aspects of all metazoan body plans, and comprises cell cycle control and growth, development, somatic- and germ-cell specification, cell adhesion, innate immunity and allorecognition. Notably, many of the genes associated with the emergence of animals are also implicated in cancer, which arises from defects in basic processes associated with metazoan multicellularity.
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              SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells.

              Colorectal and hepatocellular carcinomas are some of the leading causes of cancer deaths worldwide, but the mechanisms that underly these malignancies are not fully understood. Here we report the identification of SMYD3, a gene that is over-expressed in the majority of colorectal carcinomas and hepatocellular carcinomas. Introduction of SMYD3 into NIH3T3 cells enhanced cell growth, whereas genetic knockdown with small-interfering RNAs (siRNAs) in cancer cells resulted in significant growth suppression. SMYD3 formed a complex with RNA polymerase II through an interaction with the RNA helicase HELZ and transactivated a set of genes that included oncogenes, homeobox genes and genes associated with cell-cycle regulation. SMYD3 bound to a motif, 5'-CCCTCC-3', present in the promoter region of downstream genes such as Nkx2.8. The SET domain of SMYD3 showed histone H3-lysine 4 (H3-K4)-specific methyltransferase activity, which was enhanced in the presence of the heat-shock protein HSP90A. Our findings suggest that SMYD3 has histone methyltransferase activity and plays an important role in transcriptional regulation as a member of an RNA polymerase complex. Furthermore, activation of SMYD3 may be a key factor in human carcinogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                29 June 2012
                : 7
                : 6
                : e39914
                Affiliations
                [1 ]Biology Department and Centre for Structural and Functional Genomics, Concordia University, Montreal, Canada
                [2 ]MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
                [3 ]Wellcome Trust Sanger Institute, Hinxton, United Kingdom
                [4 ]Siemens Corporate Technology, Munich, Germany
                [5 ]Neuroscience Institute Cavalieri Ottolenghi, University of Torino, Torino, Italy
                [6 ]Biozentrum der Ludwig-Maximilans-Universität, Munich, Germany
                University of Cambridge, United Kingdom
                Author notes

                Conceived and designed the experiments: AC AT HM. Performed the experiments: KS GB AC. Analyzed the data: GB HM KS AT. Contributed reagents/materials/analysis tools: AT HM GB AC. Wrote the paper: HM KS GB AT. Designed the software used in analysis: AM.

                Article
                PONE-D-11-09962
                10.1371/journal.pone.0039914
                3386910
                22768168
                3db996d0-b58a-4b56-bc4e-fd92b7b16391
                Strasser et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 8 June 2011
                : 4 June 2012
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Developmental Biology
                Genetics
                Gene Expression
                DNA transcription
                Genomics
                Genome Analysis Tools
                Transcriptomes
                Molecular Cell Biology
                Cell Division
                Mitosis
                Cell Growth
                Gene Expression

                Uncategorized
                Uncategorized

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