Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase
Autor: | Stanley M. Lemon, Tsubasa Munakata, Kui Li, Mitsuyasu Nakamura, Yuqiong Liang |
---|---|
Rok vydání: | 2005 |
Předmět: |
viruses
Amino Acid Motifs Immunoblotting Molecular Sequence Data Down-Regulation RNA-dependent RNA polymerase Hepacivirus Viral Nonstructural Proteins Retinoblastoma Protein Cell Line chemistry.chemical_compound Cyclin D1 RNA polymerase Humans Immunoprecipitation Amino Acid Sequence Luciferases Promoter Regions Genetic E2F NS5B Polymerase Multidisciplinary biology RNA RNA virus Biological Sciences RNA-Dependent RNA Polymerase biology.organism_classification Molecular biology E2F Transcription Factors chemistry Mutation biology.protein |
Zdroj: | Proceedings of the National Academy of Sciences. 102:18159-18164 |
ISSN: | 1091-6490 0027-8424 |
Popis: | The retinoblastoma tumor-suppressor protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to regulate Rb function. Here, we show that Rb abundance is negatively regulated in cells containing replicating genomic RNA from hepatitis C virus, a human virus strongly associated with hepatocellular carcinoma. The viral RNA-dependent RNA polymerase NS5B forms a complex with Rb, targeting it for degradation and resulting in reduction of Rb abundance, activation of E2F-responsive promoters, and cell proliferation. NS5B contains a conserved Leu-x-Cys/Asn-x-Asp motif that is homologous to Rb-binding domains in the oncoproteins of DNA viruses. This domain overlaps the polymerase active site, and mutations within it abrogate Rb binding and reverse the effects of NS5B on E2F promoter activation and cell proliferation. These findings suggest a unique link between an oncogenic RNA virus implicated in the development of liver cancer and a critically important tumor-suppressor protein. |
Databáze: | OpenAIRE |
Externí odkaz: |