Multiple Hormone-Inducible Enhancers as Mediators of Differential Transcription

Abstract

Sets of genes under a common regulatory control in a given cell type are often differentially transcribed. The possibility that this differential transcription can be modulated by the number or strength of cis-acting regulatory sequences associated with a given gene was tested by using the glucocorticoid-responsive enhancer element associated with the mouse mammary tumor virus promoter. Results indicate that differential levels of hormone-inducible gene expression can be modulated in an additive way by the number of glucocorticoid-responsive enhancers associated with this promoter. Realization of these effects shows little preference for position of the additional elements with respect to the promoter. When sequences that bind the glucocorticoid receptor in vitro with somewhat lower affinity than the enhancer were tested, these additive effects were not detected. The results support that differential transcription of genes subject to a common regulatory control can be mediated, at least in part, by the number or strength of their associated cis-acting regulatory sequences.

Chemical kinetics of induced gene expression: activation of transcription by noncooperative binding of multiple regulatory molecules

“…Equations were generated for noncooperative binding occurring at equivalent and independent sites and by assuming a linear dependence of the induced rate of transcription on the number of regulatory molecules bound. This is in accord with recent results showing that the presence of multiple glucocorticoid-responsive enhancer sequences can differentially activate the mouse mammary tumor virus promoter in an additive fashion and that this increased hormone-responsive activity is relatively independent of the position of the enhancer sequences with respect to the promoter (Toohey et al, 1986). The equations de-veloped here give a good fit to the experimental data on steroid induction of alcohol dehydrogenase in mice and estrogen induction of conalbumin in chick oviduct.…”

“…As a result, the transcription rate increases in linear proportion to the number of receptor molecules bound. This is the simplest assumption that is in accord with the analyzed experimental data (see below), and it is also supported by recent results (Toohey et al, 1986) indicating that differential levels of hormone-inducible gene expression can be modulated in an additive way by the number of glucocorticoid-responsive enhancers associated with the mouse mammary tumor virus promoter. In the case considered here, the receptor-hormone complex affects the expression of gene G only by changing the transcription rate (i.e., the rate of production of new mRNA molecules).…”

“…Little or no induction by zinc was observed with single insertions of the regulatory element, whereas many constructions with two copies of the regulatory element were inducible, and constructions with additional copies were even more inducible. Similar results were obtained by Toohey et al (1986), who reported that levels of glucocorticoid activation of the mouse mammary tumor virus promoter were directly proportional to the number of glucocorticoid response elements upstream of the promoter sequence.…”

Sequence Elements Essential for Function of the Xenopus laevis Ribosomal DNA Enhancers

“…Thus, domain A of the enhancers and region -83 through -114 of the promoter share sequence homology and analogous 3' boundaries. Domain B of the enhancers comprises 19 bp of sequence and has no obvious homology to the gene promoter (only 5 out of 19 bases are the same when compared with the promoter in the region from positions -59 through -78). A linker scanner mutation from positions -60 through -69 severely damages the promoter, and we can conclude that this also is an essential promoter element.…”

“…Similar proportional effects have been seen with enhancers for RNA polymerase II promoters. Two examples are the metal response element of the metallothionein promoter (17) and the glucocorticoid response element of the mouse mammary tumor virus long terminal repeat (19).…”