title: Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression.
abstract: Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy.
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Tarangelo
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Lo
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Teng
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eunsun
authors.initials: E
authors.lastname: Kim
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Le
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Watson
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Pichai
authors.initials: P
authors.lastname: Raman
authors.affiliation: Department of Medicine, University Hospital of Munich, Munich 81675, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ehmer
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Viatour
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C525849:TIP48 protein, mouse; C525850:TIP49 protein, mouse; D004265:DNA Helicases