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Journal ArticleDOI

Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus.

Jonathan Ham, Axel Thomson1, Maurice Needham1, Paul Webb1, Malcolm G. Parker1 
24 Jun 1988-Nucleic Acids Research (Oxford University Press)-Vol. 16, Iss: 12, pp 5263-5276
TL;DR: Mutational analysis of the left half of the palindrome showed that a perfect dyad symmetry is not required for optimum activity as a steroid response element, and the minimum sequence requirements for a hormone response were analysed.
Abstract: We have characterized steroid response elements in mouse mammary tumour virus (MMTV) by transient transfection. Four partial inverted repeats of the sequence TGTTCT function as response elements for androgen, as well as for glucocorticoid and progestins, although the relative hormone inductions mediated by each oligonucleotide were different. Mutational analysis of the left half of the palindrome showed that a perfect dyad symmetry is not required for optimum activity as a steroid response element. To investigate potential interactions between steroid receptors and transcription factors we have analysed the minimum sequence requirements for a hormone response. Interestingly, a single 15 bp steroid response element and a TATA box are sufficient for steroid inductions. When the distance between the two elements was increased by up to two turns of the helix the hormone induction initially increased and then gradually declined with no obvious periodicity.
Citations
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Journal ArticleDOI
10 Feb 1989-Cell
TL;DR: The location, orientation, and structure of the hormone regulatory elements (HRE) in nine hormonally modulated genes is described and a model for the interaction is proposed in which a dimer of the receptor in head-to-head orientation binds to the inverted symmetry element of the HRE.

3,331 citations

Journal ArticleDOI
TL;DR: Receptors for retinoic acid, vitamin D3 and the steroid and thyroid hormones belong to a family of ligand-activated enhancer-binding factors which are composed of a number of functional domains required for ligand and DNA binding, nuclear translocation, dimerization and trans -activation of transcription.

987 citations

Journal ArticleDOI
30 Jun 1989-Cell
TL;DR: These findings localize structural determinants required for discrimination of HRE sequence and half-site spacing, respectively, and suggest a simple pathway for the coevolution of receptor DNA binding domains and hormone-responsive gene networks.

955 citations

Journal ArticleDOI
TL;DR: There is a consensus that one major function is to inactivate receptor by blocking DNA binding, and posttranslational modifications such as phosphorylation have been postulated to modulate several functional properties of steroid receptors.
Abstract: Steroid receptors are a class of molecules that function as both signal transducers and transcription factors. From cloned sequences it is apparent that steroid receptors and other transcription factors belong to a superfamily of proteins that appear to function by similar mechanisms. Functional domains for hormone and DNA binding, and for transcriptional activation, have been defined for several receptors. In some cases, specific amino acids required for function have been identified. The multi-functional steroid receptor molecules are modular in nature in that domains function independently of structural position in receptor molecules and can even function after insertion into unrelated transactivation proteins. The mechanism of receptor action is complex and multistage and a number of unanswered questions remain to be defined. Receptors are inactive in the absence of hormone in vivo; the proposed components of this inactive complex include several proteins and RNA. Theories on the physiological role of HSP 90 in this complex range from an artifactual interaction to an absolute conformational requirement for hormone binding. Although its function has not been demonstrated clearly yet, there is a consensus that one major function is to inactivate receptor by blocking DNA binding. Most of the steroid receptors appear to be nuclear in the absence of hormone. The transformation process produces a receptor molecule that is capable of specific DNA binding and transcriptional activation. The specificity of DNA binding is conferred by as few as three amino acids in the first finger of the C1 region. Receptors appear to bind to DNA as dimers although whether dimers are preformed in cytoplasm remains unknown. Although the DNA binding domain is required for gene activation, other regions of the molecule in the carboxyl and amino terminus enhance activation function. Important interactions of steroid receptors with other receptors and unrelated transcription factors has been proposed and most certainly occurs. Finally, posttranslational modifications such as phosphorylation have been postulated to modulate several functional properties of steroid receptors.

816 citations

Journal ArticleDOI
TL;DR: The tentative conclusion is drawn that the specificity of the hormonal response in different cells results from a combination of developmental restrictions both in the accessibility of genomic sequence and in the repertoire of regulatory proteins present in each particular cell.
Abstract: GENE regulation by steroid hormones is mediated by binding of the hormone ligand to the corresponding receptor that triggers a complex set of interactions of the hormone receptors with each other, with DNA in chromatin, and with a variety of other proteins. In this review we attempt to summarize what is known about these interactions using as the main example the regulation of mouse mammary tumor virus transcription by glucocorticoids and progestins. We describe in some detail the interaction of monomers and homodimers of the steroid receptors with their recognition sequences, and the molecular mechanism used to discriminate between the responsive elements for glucocorticoids/progestins and estrogens. We then review the interactions between homologous and heterologous hormone receptors on complex hormone regulatory regions, before devoting some attention to the synergistic and inhibitory interactions of hormone receptors with other transcription factors. Finally we briefly summarize some of the possible m...

761 citations