title: Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.
abstract: Robust mechanisms to control cell proliferation have evolved to maintain the integrity of organ architecture. Here, we investigated how two critical proliferative pathways, Myc and E2f, are integrated to control cell cycles in normal and Rb-deficient cells using a murine intestinal model. We show that Myc and E2f1-3 have little impact on normal G1-S transitions. Instead, they synergistically control an S-G2 transcriptional program required for normal cell divisions and maintaining crypt-villus integrity. Surprisingly, Rb deficiency results in the Myc-dependent accumulation of E2f3 protein and chromatin repositioning of both Myc and E2f3, leading to the 'super activation' of a G1-S transcriptional program, ectopic S phase entry and rampant cell proliferation. These findings reveal that Rb-deficient cells hijack and redeploy Myc and E2f3 from an S-G2 program essential for normal cell cycles to a G1-S program that re-engages ectopic cell cycles, exposing an unanticipated addiction of Rb-null cells on Myc.
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Huayang
authors.initials: H
authors.lastname: Liu
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Arunima
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pécot
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Daniel
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hemmelgarn
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Reyes
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fackler
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Amneet
authors.initials: A
authors.lastname: Bajwa
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Raleigh
authors.initials: R
authors.lastname: Kladney
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Koivisto
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Computer Science and Engineering, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Machiraju
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sáenz-Robles
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cantalupo
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA [2] Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA [3] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000818:Animals; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D050684:E2F Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation; D005838:Genotype; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; C490840:E2f3 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein