Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis

Crawford, Nigel P.S.; Qian, Xiaolan; Ziogas, Argyrios; Papageorge, Alex G.; Boersma, Brenda J.; Walker, Renard C.; Lukes, Luanne; Rowe, William; Zhang, Jinghui; Ambs, Stefan; Lowy, Douglas R.; Anton‐Culver, Hoda; Hunter, Kent W.

doi:10.1371/journal.pgen.0030214

Cited by 84 publications

(96 citation statements)

References 38 publications

(64 reference statements)

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“…Identification of RRP1B as a promoter of apoptosis may also suggest an explanation for the observation of higher survival in breast cancers with an expression profile driven by high RRP1B expression (23,68). RRP1B may be an important factor in apoptotic response to genotoxic agents and aberrant proliferation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…RRP1B is related to RRP1 (ribosomal RNA processing 1), a protein involved in ribosomal biogenesis localized to the nucleolus (19 -22). Recent data have shown that RRP1B is involved in suppression of metastasis, and a gene expression profile obtained following its overexpression predicted survival in breast cancers (23). However, the mechanism of how RRP1B reduces tumor burden remains unclear.…”

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Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Paik

Wang

Liu

et al. 2010

Journal of Biological Chemistry

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Regulation of the E2F family of transcription factors is important in control of cellular proliferation; dysregulation of the E2Fs is a hallmark of many cancers. One member of the E2F family, E2F1, also has the paradoxical ability to induce apoptosis; however, the mechanisms underlying this selectivity are not fully understood. We now identify a nucleolar protein, RRP1B, as an E2F1-specific transcriptional target. We characterize the RRP1B promoter and demonstrate its selective response to E2F1. Consistent with the activation of E2F1 activity upon DNA damage, RRP1B is induced by several DNA-damaging agents. Importantly, RRP1B is required for the expression of certain E2F1 proapoptotic target genes and the induction of apoptosis by DNA-damaging agents. This activity is mediated in part by complex formation between RRP1B and E2F1 on selective E2F1 target gene promoters. Interaction between RRP1B and E2F1 can be found inside the nucleolus and diffuse nucleoplasmic punctates. Thus, E2F1 makes use of its transcriptional target RRP1B to activate other genes directly involved in apoptosis. Our data also suggest an underappreciated role for nucleolar proteins in transcriptional regulation.E2F1 is a critical regulator of DNA damage response and apoptosis. As part of the E2F family of transcription factors, E2F1 is also involved in regulation of a wide array of genes important for cell cycle progression and other functions (1). Paradoxically, E2F1 has the unique ability to induce apoptosis (2). Overexpression of E2F1 ex vivo leads to apoptosis of breast cancer and other cells (3-5). Deletion of E2F1 in vivo shows a defect in thymocyte apoptosis and increased tumor incidence (6, 7). An endogenous role for E2F1 apoptosis is illustrated by its activation and stabilization by genotoxic stimuli. Overexpression of E2F1 sensitizes cells to radiation and chemotherapy (8, 9). DNA damage activates E2F1 expression and induces E2F1 stabilization through phosphorylation by DNA damage-responsive kinases ATM (ataxia telangiectasia mutated) (10) and Chk2 (checkpoint kinase 2) (11) and through acetylation (12, 13). E2F1 transactivates proapopotic genes, such as p73 (14, 15), Apaf-1 (16), and caspases (16) independently of p53 and cooperates with p53 through transactivation of p19 ARF (17). Investigation of how E2F1 specifically regulates apoptosis through selective transcriptional regulation vis-à-vis other E2F family members may reveal targets for future study that might improve the sensitivity of cancer to radiotherapy and chemotherapy. We therefore attempted to identify genes specifically regulated by E2F1 that potentially regulate E2F1-induced apoptosis. Previously, the Helin group published a microarray data set in which expression profiles were compared between cells that overexpressed E2F1, E2F2, and E2F3 (18). We screened their data set to include only those genes that were significantly induced by E2F1 but whose expression did not change more than 1-fold either positively or negatively upon E2F2 or E2F3 overexpression. The list o...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Paik

Wang

Liu

et al. 2010

Journal of Biological Chemistry

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“…TGFA, a gene known to be regulated by E2 (Fontana et al 1992) and overexpressed in endometrial cancer (Niikura et al 1996), is up-regulated by E2, GEN, and BPA. RRP1B, up-regulated only by E2, is thought to play a role in ribosomal RNA processing and may be involved in metastatic potential (Crawford et al 2007). SLC22A5, a carnitine transporter associated with autoimmune diseases (Peltekova et al 2004;Santiago et al 2006), is significantly up-regulated by E2 only but shows similar changes after GEN and BPA treatment.…”

Section: à4mentioning

confidence: 99%

Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner

et al. 2012

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Endogenous estrogens that are synthesized in the body impact gene regulation by activating estrogen receptors in diverse cell types. Exogenous compounds that have estrogenic properties can also be found circulating in the blood in both children and adults. The genome-wide impact of these environmental estrogens on gene regulation is unclear. To obtain an integrated view of gene regulation in response to environmental and endogenous estrogens on a genome-wide scale, we performed ChIP-seq to identify estrogen receptor 1 (ESR1; previously estrogen receptor α) binding sites, and RNA-seq in endometrial cancer cells exposed to bisphenol A (BPA; found in plastics), genistein (GEN; found in soybean), or 17β-estradiol (E2; an endogenous estrogen). GEN and BPA treatment induces thousands of ESR1 binding sites and >50 gene expression changes, representing a subset of E2-induced gene regulation changes. Genes affected by E2 were highly enriched for ribosome-associated proteins; however, GEN and BPA failed to regulate most ribosome-associated proteins and instead enriched for transporters of carboxylic acids. Treatment-dependent changes in gene expression were associated with treatment-dependent ESR1 binding sites, with the exception that many genes up-regulated by E2 harbored a BPA-induced ESR1 binding site but failed to show any expression change after BPA treatment. GEN and BPA exhibited a similar relationship to E2 in the breast cancer line T-47D, where cell type specificity played a much larger role than treatment specificity. Overall, both environmental estrogens clearly regulate gene expression through ESR1 on a genome-wide scale, although with lower potency resulting in less ESR1 binding sites and less gene expression changes compared to the endogenous estrogen, E2.

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“…To explore the detailed mechanisms of influenza virus transcription, we focused on the candidate host proteins with potential functions in the regulation of cellular transcription or RNA processing, since influenza virus transcription relies on host transcription (13). From the list, we focused on the rRNA processing 1 homolog B (RRP1B) gene, which was previously identified as a susceptibility gene for breast cancer progression and metastasis (14). RRP1B is a multifunctional protein that has been implicated in several biological processes.…”

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A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

Hsu

Lee

et al. 2015

J Virol

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Influenza A virus (IAV) undergoes RNA transcription by a unique capped-mRNA-dependent transcription, which is carried out by the viral RNA-dependent RNA polymerase (RdRp), consisting of the viral PA, PB1, and PB2 proteins. However, how the viral RdRp utilizes cellular factors for virus transcription is not clear. Previously, we conducted a genome-wide pooled short hairpin RNA (shRNA) screen to identify host factors important for influenza A virus replication. Ribosomal RNA processing 1 homolog B (RRP1B) was identified as one of the candidates. RRP1B is a nucleolar protein involved in ribosomal biogenesis. Upon IAV infection, part of RRP1B was translocated from the nucleolus to the nucleoplasm, where viral RNA synthesis likely takes place. The depletion of RRP1B significantly reduced IAV mRNA transcription in a minireplicon assay and in virus-infected cells. Furthermore, we showed that RRP1B interacted with PB1 and PB2 of the RdRp and formed a coimmunoprecipitable complex with RdRp. The depletion of RRP1B reduced the amount of capped mRNA in the RdRp complex. Taken together, these findings indicate that RRP1B is a host factor essential for IAV transcription and provide a target for new antivirals. IMPORTANCEInfluenza virus is an important human pathogen that causes significant morbidity and mortality and threatens the human population with epidemics and pandemics every year. Due to the high mutation rate of the virus, antiviral drugs targeting viral proteins might ultimately lose their effectiveness. An alternative strategy that explores the genetic stability of host factors indispensable for influenza virus replication would thus be desirable. Here, we characterized the rRNA processing 1 homolog B (RRP1B) protein as an important cellular factor for influenza A virus transcription. We showed that silencing RRP1B hampered viral RNA-dependent RNA polymerase (RdRp) activity, which is responsible for virus transcription and replication. Furthermore, we reported that RRP1B is crucial for RdRp binding to cellular capped mRNA, which is a critical step of virus transcription. Our study not only provides a deeper understanding of influenza virus-host interplay, but also suggests a potential target for antiviral drug development.

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Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis

Cited by 84 publications

References 38 publications

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

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