Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase

Tsubasa Munakata, Mitsuyasu Nakamura, Yuqiong Liang, Kui Li, Stanley M. Lemon

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18159-18164
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005
Externally publishedYes

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RNA Replicase
Retinoblastoma
Hepacivirus
Tumor Suppressor Proteins
Down-Regulation
RNA Viruses
Oncogene Proteins
Cell Proliferation
DNA Tumor Viruses
E2F Transcription Factors
Neoplasms
Retinoblastoma Protein
Oncogenic Viruses
DNA Viruses
Viral RNA
Liver Neoplasms
Hepatocellular Carcinoma
Catalytic Domain
RNA
Apoptosis

All Science Journal Classification (ASJC) codes

  • General

Cite this

Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. / Munakata, Tsubasa; Nakamura, Mitsuyasu; Liang, Yuqiong; Li, Kui; Lemon, Stanley M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 50, 13.12.2005, p. 18159-18164.

Research output: Contribution to journalArticle

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