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(American Journal of Pathology. 1999;155:285-292.)
© 1999 American Society for Investigative Pathology

Regular Articles

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

Jindrich Cinatl Jr.^*, Ruslan Kotchetkov^*, Martin Scholz^*, Jaroslav Cinatl, Jens-Uwe Vogel^*, Pablo Hernáiz Driever and Hans Wilhelm Doerr^*

From the Zentrum der Hygiene,^*
Institut für Medizinische Virologie, Zentrum für Kinderheilkunde und Jugendmedizin,
Abteilung Pädiatrische Hämatologie und Onkologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany, and Department of Neurosurgery,
Georgetown University Medical Center, Washington, D.C.

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 wild-type 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.

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