Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 K1 gene.
Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 K1 gene.
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DOI：
10.1093/jnci/94.12.926
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发表时间：
2002-06
期刊：
影响因子：
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通讯作者：
O. Prakash;Zhen-ya Tang;Xiaochang Peng;R. Coleman;J. Gill;G. Farr;F. Samaniego
中科院分区：
文献类型：
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作者：
O. Prakash;Zhen-ya Tang;Xiaochang Peng;R. Coleman;J. Gill;G. Farr;F. Samaniego
背景人类疱疹病毒8型(HHV-8，又称卡波西肉瘤相关疱疹病毒)的K1基因编码一种跨膜信号蛋白，可引起细胞激活事件。为了评估K1在HHV-8相关致病机制中的潜在作用，我们在猴病毒40启动子的转录控制下制备了表达HHV-8 K1基因的转基因小鼠。方法建立3个独立杂合子转基因K1小鼠品系。分析了小鼠脾、胸腺淋巴细胞和肿瘤组织中参与炎症和免疫反应的细胞因子的表达，包括肿瘤坏死因子-α(TNF-α)、白介素6(IL-6)、碱性成纤维细胞生长因子(BFGF)和白介素12(IL-12)；转录因子核因子-kappaB(NF-kappaB)和B细胞特异性转录因子Oct-2的激活；以及B细胞受体诱导的信号转导通路中Src和Syk家族激酶的激活。结果逆转录聚合酶链式反应显示，K1转基因小鼠脑组织中碱性成纤维细胞生长因子的表达明显高于非转基因小鼠，而肿瘤坏死因子α和白介素6的表达无明显差异。当用脂多糖攻击时，K1转基因小鼠的血清IL-12诱导量比非转基因小鼠低得多。来自K1转基因小鼠的B淋巴细胞，而不是来自非转基因小鼠的B淋巴细胞，显示出对NF-kappaB和Oct-2的结构性激活。K1在人B淋巴细胞中的表达可刺激核因子-kappaB依赖的启动子活性。来自K1转基因小鼠的B淋巴细胞也显示出Lyn的磷酸化增加，Lyn活性增强。K1转基因小鼠的肿瘤表现出梭形细胞肉瘤样瘤和恶性浆母细胞淋巴瘤的特征。淋巴瘤中细胞因子、转录因子和Lyn激酶的活性模式与K1转基因小鼠的B淋巴细胞相似。结论K1可能参与了核因子-kappaB信号的激活。K1小鼠非恶性淋巴细胞中核因子-kappaB活性的增强及其在这些小鼠淋巴瘤肿瘤中的持久性表明，K1小鼠可能是一种癌前病变模型。
BACKGROUND The K1 gene of human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) encodes a transmembrane signaling protein that elicits cellular activation events. To evaluate the potential role of K1 in HHV-8-associated pathogenesis, we produced transgenic mice expressing the HHV-8 K1 gene under the transcriptional control of the simian virus 40 promoter. METHODS Three independent heterozygous transgenic K1 mouse lines were generated from founder mice. Mouse splenic and thymic lymphocytes and tumor tissues were analyzed for the expression of cytokines involved in inflammatory and immune responses, including tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and interleukin 12 (IL-12); for the activation of the transcription factors nuclear factor-kappaB (NF-kappaB) and the B cell-specific transcription factor Oct-2; and for the activation of the Src and Syk family kinases, components of B-cell receptor-induced signal-transduction pathways. RESULTS Expression of bFGF was increased in K1-transgenic mice as compared with nontransgenic mice, whereas expression of TNF-alpha and IL-6 did not differ using reverse transcriptase-polymerase chain reaction. K1-transgenic mice showed substantially less serum IL-12 induction than did nontransgenic mice when challenged with a lipopolysaccharide. B lymphocytes from K1-transgenic mice but not from nontransgenic mice showed constitutive activation of NF-kappaB and Oct-2. K1 expression in human B lymphocytes stimulated NF-kappaB-dependent promoter activity. B lymphocytes from K1-transgenic mice also showed increased phosphorylation of Lyn, a Src family tyrosine kinase, and enhanced Lyn activity. Tumors in K1-transgenic mice showed features indicative of a spindle-cell sarcomatoid tumor and a malignant plasmablastic lymphoma. The pattern of cytokine, transcription factor, and Lyn kinase activity in the lymphoma was similar to that in B lymphocytes from K1-transgenic mice. CONCLUSION K1 may be involved in the activation of NF-kappaB signaling. The enhanced NF-kappaB activity in nonmalignant lymphocytes of K1 mice and its persistence in lymphoma tumors of these mice suggest that the K1 mouse may be a model of premalignancy.