Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease

Details

Serval ID
serval:BIB_09941541BCC8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease
Journal
Oncogene
Author(s)
Knecht  H., Berger  C., McQuain  C., Rothenberger  S., Bachmann  E., Martin  J., Esslinger  C., Drexler  H. G., Cai  Y. C., Quesenberry  P. J., Odermatt  B. F.
ISSN
0950-9232 (Print)
Publication state
Published
Issued date
11/1999
Volume
18
Number
50
Pages
7161-7
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov 25
Abstract
The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). However, no differences in clinical presentation and course are found between EBV positive and EBV negative forms of HD suggesting a common pathogenetic mechanism. We have studied the LMP1 associated signaling pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of LMP1 is associated with the formation of multinuclear RS cells. Dominant negative inhibition of NF-kappa B mediated signaling at the step of I kappa B-alpha phosphorylation results in increased cell death with only a few typical RS cells resistant to overexpression of the dominant negative inhibitor I kappa B-alpha-N delta 54. However, dominant negative inhibition of NF-kappa B mediated signaling at the early step of TRAF2 interaction results in the formation of multinuclear cells in both cell lines and, in addition, in clusters of small mononuclear cells in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD-inhibitor of the JNK signal transduction pathway is restricted to small cells and never observed in RS cells. These small cells undergo apoptosis as shown by the TUNEL technique. Apoptosis of small cells is still observed after co-transfection of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused nuclear masses are identified suggesting that specific inhibition of JNK leads also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling pathway is also important in the formation of Reed-Sternberg cells. Our findings are consistent with a model where all three LMP1 associated functions, i.e. NF-kappa B mediated transcription, TRAF2 dependent signaling, and c-Jun activation act as a common pathogenetic denominator of both EBV negative and EBV positive HD.
Keywords
Herpesvirus 4, Human/*isolation & purification Hodgkin Disease/*metabolism/pathology/virology Humans Receptors, Tumor Necrosis Factor/metabolism Reed-Sternberg Cells/*metabolism *Signal Transduction Viral Matrix Proteins/*metabolism
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 14:36
Last modification date
20/08/2019 12:31
Usage data