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https://doi.org/10.1172/JCI87583
Title: | Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma | Authors: | Kent, L.N Bae, S Tsai, S.-Y Tang, X Srivastava, A Koivisto, C Martin, C.K Ridolfi, E Miller, G.C Zorko, S.M Plevris, E Hadjiyannis, Y Perez, M Nolan, E Kladney, R Westendorp, B De Bruin, A Fernandez, S Rosol, T.J Pohar, K.S Pipas, J.M Leone, G |
Keywords: | transcription factor E2F1 transcription factor E2F3 transcriptome E2f1 protein, mouse E2f3 protein, mouse transcription factor E2F1 transcription factor E2F3 tumor protein animal model animal tissue Article cancer incidence cancer prognosis cancer survival chromatin chromatin immunoprecipitation controlled study copy number variation disease course DNA microarray e2f1 gene e2f3 gene epigenetics female gain of function mutation gene gene dosage gene expression gene locus gene mapping gene mutation genetic gain genetic transcription genetic variability histopathology human human cell immunoblotting immunohistochemistry liver cell carcinoma male mouse mutation rate nonhuman polymerase chain reaction protein expression tumor volume animal genetics knockout mouse liver tumor metabolism tumor gene Animals Carcinoma, Hepatocellular E2F1 Transcription Factor E2F3 Transcription Factor Gene Dosage Genes, Neoplasm Humans Liver Neoplasms Mice Mice, Knockout Neoplasm Proteins |
Issue Date: | 2017 | Publisher: | American Society for Clinical Investigation | Citation: | Kent, L.N, Bae, S, Tsai, S.-Y, Tang, X, Srivastava, A, Koivisto, C, Martin, C.K, Ridolfi, E, Miller, G.C, Zorko, S.M, Plevris, E, Hadjiyannis, Y, Perez, M, Nolan, E, Kladney, R, Westendorp, B, De Bruin, A, Fernandez, S, Rosol, T.J, Pohar, K.S, Pipas, J.M, Leone, G (2017). Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. Journal of Clinical Investigation 127 (3) : 830-842. ScholarBank@NUS Repository. https://doi.org/10.1172/JCI87583 | Rights: | Attribution 4.0 International | Abstract: | Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss-and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1-and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer. | Source Title: | Journal of Clinical Investigation | URI: | https://scholarbank.nus.edu.sg/handle/10635/179227 | ISSN: | 00219738 | DOI: | 10.1172/JCI87583 | Rights: | Attribution 4.0 International |
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