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Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)
07:02

Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)

Published on: September 14, 2010

Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21CIP-1-mediated

Frederick Y Wu1, Qi-Qun Tang, Honglin Chen

  • 1Molecular Virology Laboratories, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 30, 2002
PubMed

Insights

Kaposi sarcoma-associated herpesvirus (KSHV) replication induces cell cycle arrest. The KSHV RAP protein utilizes C/EBPalpha to inhibit G(1) to S-phase progression, facilitating viral DNA replication.

Area of Science:

  • Virology
  • Cell Biology
  • Oncology

Background:

  • Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic DNA virus linked to Kaposi sarcoma and primary effusion lymphoma (PEL).
  • KSHV lytic replication is crucial for viral propagation and pathogenesis.
  • Understanding KSHV's interaction with host cell machinery is key to developing antiviral strategies.

Purpose of the Study:

  • To investigate the role of KSHV lytic cycle replication in host cell cycle regulation.
  • To identify the specific viral and cellular factors involved in KSHV-induced cell cycle arrest.
  • To elucidate the mechanism by which KSHV manipulates the cell cycle to promote viral replication.

Main Methods:

  • Induction of KSHV lytic cycle in PEL cells.
  • Analysis of cell cycle progression using flow cytometry.
  • Western blotting to detect protein expression (C/EBPalpha, p21).
  • In vitro binding assays and cotransfection experiments to assess protein interactions and promoter activity.
  • Use of recombinant adenovirus to express KSHV RAP protein in human fibroblasts.
  • Functional studies in C/EBPalpha-deficient cells and RAP mutants.

Main Results:

  • KSHV lytic replication in PEL cells induces G(1) cell cycle arrest.
  • Expression of KSHV early lytic protein RAP coincides with increased nuclear levels of C/EBPalpha and p21(CIP-1).
  • KSHV RAP protein binds to C/EBPalpha and stimulates C/EBPalpha-mediated promoter activity.
  • RAP induces C/EBPalpha and p21 expression and inhibits G(1) to S-phase progression in primary human fibroblasts.
  • C/EBPalpha and the RAP interaction domain are essential for RAP-mediated cell cycle inhibition.

Conclusions:

  • KSHV utilizes its early lytic protein RAP to induce G(1) cell cycle arrest in host cells.
  • The mechanism involves the interaction of RAP with C/EBPalpha, leading to p21-mediated inhibition of G(1) to S-phase progression.
  • This host cell cycle manipulation likely facilitates KSHV DNA replication and viral propagation.

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