Human Cytomegalovirus Infection Decreases Expression of Thrombospondin-1 Independent of the Tumor Suppressor Protein p53

Abstract

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 immediateearly 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. (Am J Pathol 1999, 155:285-292) Human cytomegalovirus (HCMV) has been implicated in the etiology of several human malignancies based on seroepidemiological studies and the presence of HCMV DNA, RNA, and/or antigens in tumor tissues. 1 The definitive establishment of a direct causative role for HCMV in the course of the malignancies has been elusive as HCMV components were not detected after long-term subculture of tumor tissues. 1 Moreover, the presence of genetic information in human tumors is difficult to interpret as HCMV can cause latent infection of numerous organs in a high percentage of normal individuals. 1 On the other hand, in vitro infection of cells with HCMV influences the expression of different cellular genes and/or function of cellular proteins that are associated with cell growth, differentiation, and apoptosis. These changes result in disturbance of normal tissue homeostasis, which indirectly may promote tumor growth. [2][3][4][5][6] In particular, in vitro studies have shown that HCMV gene products such as immediate-early (IE) proteins or morphological transforming region II oncoprotein bind wild-type p53 tumor suppressor protein and thereby down-regulate p53-activated transcription. [7][8][9][10][11]

Elongation Factor ELL (Eleven-Nineteen Lysine-rich Leukemia) Acts as a Transcription Factor for Direct Thrombospondin-1 Regulation

“…As such, the lack of normalization might account for the discrepancy between our results and those in the literature (39). Indeed, subsequent reports did not support a relationship between TSP-1 expression levels and with p53 status (47,48).…”

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

“…While it is reasonable to speculate that targeting of p53 for degradation by E6 can account for the changes in expression levels of the factors that we have observed, other mechanisms are possible. The regulation of thrombospondin-1 via p53 seems to be cell type and tumor type specific (Bouck, 1996;Cinatl Jr, et al, 1999). The regulation of VEGF by E6 can occur via a p53-independent mechanism.…”

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…CMV is able to induce interleukin 8 (IL-8), a promoter of tumor angiogenesis, in leukemia and glioma cells, through NF-κB/AP-1-mediated transactivation of the IL-8 promoter (Murayama et al 2000). CMV also suppresses the expression of angiogenesis inhibitors (thrombospondins) in glioma cells (Cinatl et al 1999). …”