The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor.
The nuclear (steroid/thyroid/retinoid) receptor superfamily is a set of evolutionarily related ligand-inducible regulators of transcription. One subgroup within this family has been termed the orphan receptors because the potential ligands required for their activity have not been identified. We have cloned a novel orphan receptor, MINOR, which is mitogen inducible in a variety of cell types. Unlike NGFI-B/Nur77, another mitogen-inducible orphan receptor, MINOR gene expression is inhibited in Jurkat cells by the immunosuppressant cyclosporin A, suggesting that it is regulated by distinct second messenger pathways. The conservation of the DNA-binding domain between MINOR and other orphan receptors is reflected in the fact that they are able to bind to the same sequence, AAAG-GTCA [termed the NBRE (NGFI-B response element)]. The marked divergence in other domains, particularly the N-terminal putative transactivation domain, may result in qualitative or quantitative differences in other functions among these proteins. One of these differences may be the apparent squelching of peak levels of MINOR-mediated transcription by supraoptimal levels of MINOR expression, an effect not obtained with NGFI-B/Nur77. When MINOR i coexpressed with submaximal levels of NGFI-B/Nur77, synergistic or additive levels of reporter gene expression are obtained. However, at maximal levels of NGFI-B/Nur77 expression, MINOR antagonizes the level of reporter gene expression in a dose-dependent fashion. These cooperative/competitive interactions, together with the nonidentical expression patterns of MINOR and NGFI-B/Nur77, suggest complexity in the regulation of genes responsive to orphan receptors which bind to the NBRE.
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Department of Pathology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Irving
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015139:Blotting, Southern; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016366:Open Reading Frames; D012333:RNA, Messenger / Q000032:analysis / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification*; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D017385:Sequence Homology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification* / Q000494:pharmacology; D014981:Xenopus
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D008934:Mitogens; C539821:NR4A1 protein, human; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D016572:Cyclosporine; D004247:DNA