Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53
Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53
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DOI：
10.1016/s0002-9440(10)65122-x
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发表时间：
1999-07-01
影响因子：
6
通讯作者：
Doerr, HW
中科院分区：
文献类型：
--
作者：
Cinatl, J;Kotchetkov, R;Doerr, HW
血小板反应蛋白-1（TSP-1）是一种有效的血管生成抑制剂。已经显示TSP-1基因的启动子序列可以被野生型肿瘤抑制蛋白p53反式激活。由于人巨细胞病毒（HCMV）感染使各种细胞类型的野生型p53失活，我们研究了HCMV感染是否与TSP-1产生减少有关。我们发现，与积累的p53，TSP-1的mRNA和蛋白表达显着减少，在HCMV感染培养的人成纤维细胞。为了确定观察到的TSP-1抑制是否依赖于p53失活，用HCMV感染p53缺陷型星形细胞瘤细胞系U373 MG。在这些细胞中，TSP-1的表达也显着减少HCMV感染，而表达的p53突变体的变体保持不变。在两种细胞系中，TSP-1 mRNA表达的降低发生在感染后早期（4小时），表明HCMV在HCMV DNA复制之前的感染的立即早期阶段抑制TSP-1转录。更昔洛韦对HCMV DNA合成的抑制不影响TSP-1的降低，而与HCMV立即早期mRNA互补的反义寡核苷酸ISIS 2922，完全阻止了HCMV介导的TSP-1抑制。这些研究结果强烈表明，由于p53非依赖性TSP-1表达下调，HCMV在血管生成的调制中发挥了新的作用。
Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis. It has been shown that promoter sequences of the TSP-1 gene can be transactivated by the wild-type tumor suppressor protein p53. As human cytomegalovirus (HCMV) infection inactivates wildtype p53 of various cell types, we investigated whether HCMV infection is associated with reduced TSP-1 production. We found, in conjunction with accumulated p53, that TSP-1 mRNA and protein expression was significantly reduced in HCMV-infected cultured human fibroblasts. To determine whether the observed TSP-1 suppression depends on p53 inactivation, the p53-defective astrocytoma cell line U373MG was infected with HCMV. In these cells TSP-1 expression was also significantly reduced by HCMV infection whereas expression of the p53 mutant variant remained unaltered. In both cell lines the decreased expression of TSP-1 mRNA occurred early after infection (4 hours), indicating that HCMV inhibits TSP-1 transcription during the immediate-early phase of infection before HCMV DNA replication, Inhibition of HCMV DNA synthesis by ganciclovir did not influence TSP-1 reduction whereas the antisense oligonucleotide ISIS 2922, complementary to HCMV immediate-early mRNA, completely prevented the HCMV-mediated TSP-1 suppression. These findings strongly suggest a novel role for HCMV in the modulation of angiogenesis due to p53-independent down-regulation of TSP-1 expression.