Simian virus 40 late gene expression is regulated by members of the steroid/thyroid hormone receptor superfamily.
Transcription of the late genes of simian virus 40 (SV40) is repressed during the early phase of the lytic cycle of infection of binding of cellular factors, called IBP-s, to the SV40 late promoter; repression is relieved after the onset of viral DNA replication by titration of these repressors. Preliminary data indicated that one of the major components of IBP-s was human estrogen-related receptor 1 (hERR1). We show here that several members of the steroid/thyroid hormone receptor superfamily, including testis receptor 2, thyroid receptor alpha 1 in combination with retinoid X receptor alpha, chicken ovalbumin upstream promoter transcription factors 1 and 2 (COUP-TF1 and COUP-TF2), as well as hERR1, possess the properties of IBP-s. These receptors bind specifically to hormone receptor binding sites present in the SV40 major late promoter. Recombinant COUP-TF1 specifically represses transcription from the SV40 major late promoter in a cell-free transcription system. Expression of COUP-TF1, COUP-TF2, or hERR1 in monkey cells results in repression of the SV40 late promoter, but not the early promoter, in the absence of the virally encoded large tumor antigen. Overexpression of COUP-TF1 leads to a delay in the early-to-late switch in SV40 gene expression during the lytic cycle of infection. Thus, members of this superfamily can play major direct roles in regulating expression of SV40. Possibly, natural or synthetic ligands to these receptors can serve as antiviral drugs. Our findings also provide the basis for the development of assays to screen for the ligands to testis receptor 2 and hERR1.
Zuo
F
F
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706-1599, USA.
Mertz
J E
JE
D000957:Antigens, Viral, Tumor / Q000378:metabolism; D001483:Base Sequence; D051838:COUP Transcription Factor I; D051836:COUP Transcription Factors; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D005812:Genes, Switch; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D047488:Retinoid X Receptors; D013539:Simian virus 40 / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000957:Antigens, Viral, Tumor; D051838:COUP Transcription Factor I; D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; C059917:ERD5 protein, human; C497589:NR2F1 protein, human; C539950:NR6A1 protein, human; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors