Cellular zinc status regulates cytomegalovirus major immediate-early promoter.
Diethylenetriaminepenta-acetic acid (DTPA) inhibits human cytomegalovirus (CMV) replication in vitro, although the mechanism has remained unclear. The present study shows that DTPA inhibits CMV major immediate-early (MIE) promoter activity in a luciferase reporter assay, whereas its enhancer-less promoter was not affected. The inhibitory effect of DTPA on CMV MIE promoter activity was abrogated by stoichiometric amounts of cations in the following (decreasing) order, Zn(2+)>Co(2+)>Ni(2+)>Cu(2+)>Fe(3+)>Fe(2+), but not by Mn(2+). These cations bind to DTPA and may limit the zinc-chelating capability. In the absence of DTPA, exogenous zinc activated CMV MIE promoter activity in a dose-dependent manner, but not its enhancer-less promoter. The intracellular metallothionein content of DTPA- and cation-treated cultures was significantly correlated with CMV MIE promoter activity. DTPA may inhibit CMV replication by regulating CMV MIE promoter activity through controlling the availability of cellular zinc. Since the CMV MIE promoter has no consensus sequence for a metal responsive element, a novel mechanism for metal-regulated transcription may be involved in this process.
Kanekiyo
M
M
Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, 565-0871, Osaka, Japan.
Itoh
N
N
Mano
M
M
Kawasaki
A
A
Tanaka
J
J
Muto
N
N
Tanaka
K
K
D000956:Antigens, Viral / Q000235:genetics* / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D004369:Pentetic Acid / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D015032:Zinc / Q000378:metabolism*
D000956:Antigens, Viral; D002412:Cations; D002614:Chelating Agents; D017874:Immediate-Early Proteins; C044582:immediate-early proteins, cytomegalovirus; D004369:Pentetic Acid; D008668:Metallothionein; D008156:Luciferases; D015032:Zinc