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      Redeployment of Myc and E2f1-3 drives Rb deficient cell cycles

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          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 G 1-S transitions. Instead, they synergistically control an S-G 2 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 G 1-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-G 2 program essential for normal cell cycles to a G 1-S program that re-engages ectopic cell cycles, exposing an unanticipated addiction of Rb-null cells on Myc.

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          Most cited references44

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          Identification of c-MYC as a target of the APC pathway.

          The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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            Reflecting on 25 years with MYC.

            Just over 25 years ago, MYC, the human homologue of a retroviral oncogene, was identified. Since that time, MYC research has been intense and the advances impressive. On reflection, it is astonishing how each incremental insight into MYC regulation and function has also had an impact on numerous biological disciplines, including our understanding of molecular oncogenesis in general. Here we chronicle the major advances in our understanding of MYC biology, and peer into the future of MYC research.
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              HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.

              Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                27 June 2015
                20 July 2015
                August 2015
                01 February 2016
                : 17
                : 8
                : 1036-1048
                Affiliations
                [1 ]Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
                [2 ]Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, OH 43210, USA
                [3 ]Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
                [4 ]Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
                [5 ]Department of Computer Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
                [6 ]Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
                Author notes
                [* ]Corresponding Author: Corresponding Author Information: Gustavo Leone, Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, The Ohio State University, Comprehensive Cancer Center, 460 W. 12th Ave., Room 592, Columbus, OH 43210, Telephone: 614-688-4567, FAX: 614-688-4181, Gustavo.Leone@ 123456osumc.edu
                Article
                NIHMS702897
                10.1038/ncb3210
                4526313
                26192440
                d7c7fa74-59ef-49f6-971b-0e81bf293011

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                Cell biology
                Cell biology

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