© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 20, 1725-1733,
October 20, 1999
© 1999 Oxford University Press
Expression of K13/v-FLIP Gene of Human Herpesvirus 8 and Apoptosis in Kaposi's Sarcoma Spindle Cells
Affiliations of authors: M. Stürzl, Institute of Molecular Virology, GSF-National Research Center for Environment and Health, Neuherberg, Germany, and Department of Virus Research, Max-Planck Institute for Biochemistry, Martinsried, Germany, and Bavarian Nordic Research Institute AS, Martinsried; C. Hohenadl, Institute of Molecular Virology, GSF-National Research Center for Environment and Health; C. Zietz, Institute of Pathology, Ludwig Maximilians University of Munich, Germany; E. Castanos-Velez, P. Biberfeld, Immunopathology Laboratory, Karolinska Institute, Stockholm, Sweden; A. Wunderlich, Bavarian Nordic Research Institute AS; G. Ascherl, Institute of Virology, Technical University of Munich; P. Monini, B. Ensoli, Laboratory of Virology, Istituto Superiore di Sanit|fa, Rome, Italy; P. J. Browning, Vanderbilt University Medical Center, Nashville, TN.
Correspondence to: Priv. Doz. Dr. rer. nat. Michael Stürzl, Institute of Molecular Virology, GSF-National Research Center for Environment and Health GmbH, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany (e-mail: Stuerzl{at}gsf.de).
BACKGROUND: Human herpesvirus 8 (HHV8) infection is associated with all forms of Kaposi's sarcoma (KS). The HHV8 genome locus ORFK13-72-73 (ORF = open reading frame) encodes proteins that may be important in HHV8-mediated pathogenesis, i.e., the latency-associated nuclear antigen (encoded by ORF73), viral-cyc-D (v-cyc-D), a viral homologue of cellular cyclin D (encoded by ORF72), and viral-FLIP (v-FLIP), a homologue of the cellular FLICE (Fas-associated death domain-like interleukin 1 beta-converting enzyme) inhibitory protein (encoded by ORFK13; is an inhibitor of apoptosis [programmed cell death]). Through differential splicing events, this locus expresses individual RNA transcripts that encode all three proteins (tricistronic transcripts) or just two of them (v-FLIP and v-cyc-D; bicistronic transcripts). We examined expression of these transcripts in KS tissues. METHODS: We collected tissues from patients with KS of different stages. By use of an optimized in situ hybridization procedure, we examined different ORFK13-72-73 locus transcripts in HHV8-infected cells in skin lesions and in one adjacent lymph node. Apoptosis in KS lesions was determined by use of an in situ assay. RESULTS AND CONCLUSIONS: Our results indicate the following: 1) Transcripts from the ORFK13-72-73 locus appear to be spliced differentially in latently infected KS cells in skin lesions and in HHV8-infected cells in lymph nodes; specifically, ORFK13-ORF72 bicistronic transcripts were expressed abundantly in KS cells, whereas ORFK13-ORF72-ORF73 tricistronic transcripts were detected only in lymph node cells. 2) Sequences encoding the antiapoptotic protein v-FLIP are expressed at very low levels in early KS lesions, but expression increases dramatically in late-stage lesions. 3) The increase in expression of v-FLIP-encoding transcripts is associated with a reduction in apoptosis in KS lesions. IMPLICATIONS: These data suggest that functional v-FLIP is produced in vivo and that antiapoptotic mechanisms may be involved in the rapid growth of KS lesions, where only a few cells undergoing mitosis are generally observed.
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