Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase
- Department of Microbiology and Immunology and the Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-1019
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Edited by Francis V. Chisari, The Scripps Research Institute, La Jolla, CA (received for review July 5, 2005)
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.
Footnotes
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↵ * To whom correspondence should be addressed at: Center for Hepatitis Research, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019. E-mail: smlemon{at}utmb.edu.
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Author contributions: T.M., Y.L., K.L., and S.M.L. designed research; T.M., M.N., and Y.L. performed research; M.N. and K.L. contributed new reagents/analytic tools; T.M., M.N., Y.L., K.L., and S.M.L. analyzed data; and T.M. and S.M.L. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: HCV, hepatitis C virus; Rb, retinoblastoma tumor-suppressor protein; wt, wild type.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
