title: Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts.
abstract: The transcription factor E2F is the principal target of the tumor suppressor pRB. E2F plays crucial roles not only in cell proliferation by activating growth-related genes but also in tumor suppression by activating pro-apoptotic and growth-suppressive genes. We previously reported that, in human normal fibroblasts, the tumor suppressor genes ARF, p27(Kip1) and TAp73 are activated by deregulated E2F activity induced by forced inactivation of pRB, but not by physiological E2F activity induced by growth stimulation. In contrast, growth-related E2F targets are activated by both E2F activities, underscoring the roles of deregulated E2F in tumor suppression in the context of dysfunctional pRB. In this study, to further understand the roles of deregulated E2F, we explored new targets that are specifically activated by deregulated E2F using DNA microarray. The analysis identified nine novel targets (BIM, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4 and RBBP7), many of which are involved in the p53 and RB tumor suppressor pathways. Among these genes, the BIM gene was shown to be activated via atypical E2F-responsive promoter elements and to contribute to E2F1-mediated apoptosis. Our results underscore crucial roles of deregulated E2F in growth suppression to counteract loss of pRB function.
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Hodaka
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Eiko
authors.initials: E
authors.lastname: Ozono
authors.affiliation: Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Iwanaga
authors.affiliation: Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Bradford
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Okuno
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Shimizu
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kurayoshi
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kugawa
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Toh
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ohtani
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D050684:E2F Transcription Factors / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D008565:Membrane Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins