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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3987-3994.
Prepublished online as a Blood First Edition Paper on January 21, 2005; DOI 10.1182/blood-2004-07-2781.
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Submitted July 21, 2004
Accepted January 9, 2005
Activation of Src kinase Lyn by the Kaposi sarcoma-associated herpes virus K1 protein: implications for lymphomagenesis
Om Prakash*, O R Swamy, Xiochang Peng, Zhen-Ya Tang, Li Li, Janet E Larson, J C Cohen, Javed Gill, Gist Farr, Suizhao Wang, and Felipe Samaniego
Laboratory of Molecular Oncology, Ochsner Clinic Foundation, New Orleans, LA, USA
Department of Pathology, Ochsner Clinic Foundation, New Orleans, LA, USA
Department of Lymphoma/Myeloma and Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Program in Gene Therapy and Virology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
* Corresponding author; email: oprakash{at}ochsner.org.
The K1 gene of Kaposi sarcoma-associated herpesvirus (KSHV) encodes a transmembrane glycoprotein bearing a functional immunoreceptor tyrosine-based activation motif (ITAM). Previously, we reported that the K1 protein induced plasmablastic lymphomas in K1 transgenic mice, and that these lymphomas showed enhanced Lyn kinase activity. Here, we report that systemic administration of the NF- B inhibitor Bay 11-7085 or an anti-vascular endothelial growth factor (VEGF) antibody significantly reduced K1 lymphoma growth in nude mice. Furthermore, in KVL-1 cells, a cell line derived from a K1 lymphoma, inhibition of Lyn kinase activity by the Src kinase inhibitor PP2 decreased VEGF induction, NF-B activity, and the cell proliferation index by 50%-75%. In contrast, human B-cell lymphoma BJAB cells expressing K1, but not the ITAM sequence-deleted mutant K1, showed a marked increase in Lyn kinase activity with concomitant VEGF induction and NF-B activation, indicating that ITAM sequences were required for the Lyn kinase-mediated activation of these factors. Our results suggested that K1-mediated constitutive Lyn kinase activation in K1 lymphoma cells is crucial for the production of VEGF and NF-B activation, both strongly implicated in the development of KSHV-induced lymphoproliferative disorders.
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