Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53.
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.
Zentrum der Hygiene,* Institut für Medizinische Virologie, Zentrum für Kinderheilkunde und Jugendmedizin,dagger Abteilung Pädiatrische Hämatologie und Onkologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
J
J
Cinatl
R
R
Kotchetkov
M
M
Scholz
J
J
Cinatl
J U
JU
Vogel
P H
PH
Driever
H W
HW
Doerr
D000998:Antiviral Agents / Q000494:pharmacology; D001254:Astrocytoma / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000998:Antiviral Agents; D012333:RNA, Messenger; D013873:Thionucleotides; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D015774:Ganciclovir; C091346:fomivirsen