The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors
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DOI：
10.1158/0008-5472.can-03-3653
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发表时间：
2004-04-15
期刊：
影响因子：
11.2
通讯作者：
Damania, B
中科院分区：
文献类型：
--
作者：
Wang, L;Wakisaka, N;Damania, B
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Castleman病有关。除内皮细胞和B淋巴细胞外，KSHV还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是能够引发B细胞活化的信号蛋白。我们发现KSHV K1可以诱导上皮细胞和内皮细胞表达和分泌血管内皮生长因子（VEGF）。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。我们还表明，K1诱导表达基质金属蛋白酶-9（MMP-9）在内皮细胞。对K1突变蛋白的进一步分析显示，K1胞质尾区中存在的SH 2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信号可能有助于KSHV相关的发病机制，通过旁分泌机制，促进VEGF和MMP-9分泌到周围的矩阵。
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. Upregulation 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.