title: An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia.
abstract: Induction of cell-autonomous apoptosis following oncogene-induced overproliferation is a major tumor-suppressive mechanism in vertebrates. However, the detailed mechanism mediating this process remains enigmatic. In this study, we demonstrate that dMyc-induced cell-autonomous apoptosis in the fruit fly Drosophila melanogaster relies on an intergenic sequence termed the IRER (irradiation-responsive enhancer region). The IRER mediates the expression of surrounding proapoptotic genes, and we use an in vivo reporter of the IRER chromatin state to gather evidence that epigenetic control of DNA accessibility within the IRER is an important determinant of the strength of this response to excess dMyc. In a previous work, we showed that the IRER also mediates P53-dependent induction of proapoptotic genes following DNA damage, and the chromatin conformation within IRER is regulated by polycomb group-mediated histone modifications. dMyc-induced apoptosis and the P53-mediated DNA damage response thus overlap in a requirement for the IRER. The epigenetic mechanisms controlling IRER accessibility appear to set thresholds for the P53- and dMyc-induced expression of apoptotic genes in vivo and may have a profound impact on cellular sensitivity to oncogene-induced stress.
authors.affiliation: 1] Department of Molecular Genetics and Microbiology and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA [2] Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cajal Institute, Spanish Research Council (CSIC), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Casas-Tintó
authors.affiliation: 1] Department of Molecular Genetics and Microbiology and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA [2] UF Genetics Institute, University of Florida, Gainesville, FL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics and Microbiology and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lin
authors.affiliation: Department of Molecular Genetics and Microbiology and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chung
authors.affiliation: Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Moberg
authors.affiliation: 1] Department of Molecular Genetics and Microbiology and UF Shands Cancer Center, University of Florida, Gainesville, FL, USA [2] UF Genetics Institute, University of Florida, Gainesville, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D044127:Epigenesis, Genetic; D049750:Genome, Insect; D006965:Hyperplasia / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014921:Wings, Animal / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C102284:Myc protein, Drosophila; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C474203:p53 protein, Drosophila