Constitutive NF-κB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice

Priti Chugh, Hittu Matta, Sandra Schamus, Sunny Zachariah, Arvind Kumar, James A. Richardson, Alice L. Smith, Preet M. Chaudhary

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Human herpesvirus 8 (HHV-8, also called Kaposi's sarcoma-associated herpes virus) has been linked to Kaposi's sarcoma and primary effusion lymphoma. HHV-8-encoded viral Fas-associated death domain-like IL-1-converting enzyme inhibitory protein (vFLIP) is one of the few viral proteins to be expressed in latently infected cells and plays a key role in the survival and proliferation of primary effusion lymphoma cells. Two main functions have been ascribed to HHV-8 vFLIP, inhibition of caspase 8 Fas-associated death domain-like IL-1-converting enzyme and activation of NF-σB. In this article, we demonstrate that vFLIP-expressing transgenic mice lack any of the features seen in mice deficient in caspase 8 or Fas-associated death domain protein and are not resistant to Fas-induced apoptosis. On the other hand, these mice display constitutive activation of classical and alternative NF-κB pathways, enhanced response to mitogenic stimuli, and increased incidence of lymphoma. Collectively, our results demonstrate that HHV-8 vFLIP is an oncogenic protein that mimics the signaling activities of caspase 8 during antigen receptor signaling and could contribute to the development of lymphoproliferative disorders via constitutive NF-κB activation independent of inhibition of Fas-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)12885-12890
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number36
DOIs
Publication statusPublished - Sep 6 2005

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Keywords

  • Kaposi's sarcoma-associated herpes virus
  • Primary effusion lymphoma

ASJC Scopus subject areas

  • Genetics
  • General

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