Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cancer cell (Impact Factor: 23.52). 04/2010; 17(4):376-87. DOI: 10.1016/j.ccr.2010.01.023
Source: PubMed


The RB protein family (RB, p107, and p130) has overlapping and compensatory functions in cell-cycle control. However, cancer-associated mutations are almost exclusively found in RB, implying that RB has a nonredundant role in tumor suppression. We demonstrate that RB preferentially associates with E2F target genes involved in DNA replication and is uniquely required to repress these genes during senescence but not other growth states. Consequently, RB loss leads to inappropriate DNA synthesis following a senescence trigger and, together with disruption of a p21-mediated cell-cycle checkpoint, enables extensive proliferation and rampant genomic instability. Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence.

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Available from: Ross Dickins, Feb 16, 2015
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    • "K-means clustering with the Euclidean distance was performed using MeV 4.8.1 (Saeed et al., 2003), and GO term analysis was carried out with the DAVID functional annotation tool (Dennis et al., 2003). RB enrichment in association with Cluster 20 genes (AE2 kb from the transcription start site) was determined using PAVIS (Huang et al., 2013), based on previously reported RB ChIP-seq data in OIS IMR90 cells (Chicas et al., 2010). "
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    ABSTRACT: Metabolism is closely linked with cellular state and biological processes, but the mechanisms controlling metabolic properties in different contexts remain unclear. Cellular senescence is an irreversible growth arrest induced by various stresses, which exhibits active secretory and metabolic phenotypes. Here, we show that retinoblastoma protein (RB) plays a critical role in promoting the metabolic flow by activating both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in cells that have undergone oncogene-induced senescence (OIS). A combination of real-time metabolic monitoring, and metabolome and gene expression analyses showed that OIS-induced fibroblasts developed an accelerated metabolic flow. The loss of RB downregulated a series of glycolytic genes and simultaneously reduced metabolites produced from the glycolytic pathway, indicating that RB upregulates glycolytic genes in OIS cells. Importantly, both mitochondrial OXPHOS and glycolytic activities were abolished in RB-depleted or downstream glycolytic enzyme-depleted OIS cells, suggesting that RB-mediated glycolytic activation induces a metabolic flux into the OXPHOS pathway. Collectively, our findings reveal that RB essentially functions in metabolic remodeling and the maintenance of the active energy production in OIS cells. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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    • "Association of retinoblastoma proteins is noted for a large fraction of cytoplasmic and mitochondrial promoters. Binding to each promoter from the C. elegans and human data set was analyzed by uploading peak calling files from Latorre et al. 2015, and Chicas et al. 2010 "
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    ABSTRACT: Rbf2 is a recently evolved Retinoblastoma family member in Drosophila, differing from Rbf1 especially in the C-terminus. To investigate whether the unique features of Rbf2 contribute to diverse roles in gene regulation, we performed ChIP-Seq for both Rbf2 and Rbf1 in embryos. A previous model for Rb-E2F interactions suggested that Rbf1 binds dE2F1 or dE2F2, while Rbf2 is restricted to binding to dE2F2, however, we found that Rbf2 targets approximately twice as many genes as Rbf1. Highly enriched among the Rbf2 targets were ribosomal protein genes. We tested the functional significance of this finding by assessing Rbf activity on ribosomal protein promoters and the endogenous genes. Rbf1 and Rbf2 significantly repressed expression of some ribosomal protein genes, although not all bound genes showed transcriptional effects. Interestingly, many ribosomal protein genes are similarly targeted in human cells, indicating that these interactions may be relevant for control of ribosome biosynthesis and growth. We carried out bioinformatic analysis to investigate the basis for differential targeting by these two proteins, and found that Rbf2-specific promoters have distinct sequence motifs, suggesting unique targeting mechanisms. Association of Rbf2 with these promoters appears to be independent of dE2F2/dDP, although promoters bound by both Rbf1 and Rbf2 require dE2F2/dDP. The presence of unique Rbf2 targets suggest that evolutionary appearance of this corepressor represents the acquisition of potentially novel roles in gene regulation for the RB family. Copyright © 2015 Author et al.
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    • "Genome-wide data also confirmed robust Rb binding at the Sox2 and Oct4 loci (Figure 4B, Table S2). Moreover, we found Rb binding to the regulatory regions of a number of genes involved in reprogramming and pluripotency, an observation supported by the analysis of human Rb ChIP sequencing data sets (Chicas et al., 2010) (Fig- ure "
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    ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
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