TY - JOUR
T1 - Constitutive NF-κB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice
AU - Chugh, Priti
AU - Matta, Hittu
AU - Schamus, Sandra
AU - Zachariah, Sunny
AU - Kumar, Arvind
AU - Richardson, James A.
AU - Smith, Alice L.
AU - Chaudhary, Preet M.
PY - 2005/9/6
Y1 - 2005/9/6
N2 - 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.
AB - 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.
KW - Kaposi's sarcoma-associated herpes virus
KW - Primary effusion lymphoma
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U2 - 10.1073/pnas.0408577102
DO - 10.1073/pnas.0408577102
M3 - Article
C2 - 16120683
AN - SCOPUS:24644491664
SN - 0027-8424
VL - 102
SP - 12885
EP - 12890
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -