Wang Ling, Wakisaka Naohiro, Tomlinson Christine C, DeWire Scott M, Krall Stuart, Pagano Joseph S, Damania Blossom
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Cancer Res. 2004 Apr 15;64(8):2774-81. doi: 10.1158/0008-5472.can-03-3653.
Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) has been linked to Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. In addition to endothelial cells and B lymphocytes, KSHV also has been shown to infect epithelial cells and keratinocytes. The transmembrane glycoprotein K1, encoded by the first open reading frame of KSHV, is a signaling protein capable of eliciting B-cell activation. We show that KSHV K1 can induce expression and secretion of vascular endothelial growth factor (VEGF) in epithelial and endothelial cells. Up-regulation of VEGF was mediated at the transcriptional level because expression of K1 resulted in VEGF promoter activation. We also show that K1 induces expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. Additional analyses with K1 mutant proteins revealed that the SH2 binding motifs present in the K1 cytoplasmic tail are necessary for VEGF secretion and MMP-9 induction. These results indicate that K1 signaling may contribute to KSHV-associated pathogenesis through a paracrine mechanism by promoting the secretion of VEGF and MMP-9 into the surrounding matrix.
卡波西肉瘤相关疱疹病毒（KSHV/HHV-8）与卡波西肉瘤、原发性渗出性淋巴瘤和多中心性Castleman病有关。除了内皮细胞和B淋巴细胞外，KSHV还被证明可感染上皮细胞和角质形成细胞。由KSHV的第一个开放阅读框编码的跨膜糖蛋白K1是一种能够引发B细胞活化的信号蛋白。我们发现KSHV K1可诱导上皮细胞和内皮细胞中血管内皮生长因子（VEGF）的表达和分泌。VEGF的上调是在转录水平介导的，因为K1的表达导致VEGF启动子激活。我们还发现K1可诱导内皮细胞中基质金属蛋白酶-9（MMP-9）的表达。对K1突变蛋白的进一步分析表明，K1细胞质尾部存在的SH2结合基序对于VEGF分泌和MMP-9诱导是必需的。这些结果表明，K1信号传导可能通过旁分泌机制，促进VEGF和MMP-9分泌到周围基质中，从而参与KSHV相关的发病过程。
