The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function

Webster, Nicholas J. G.; Green, Stephen; Jin, Jia; Chambon, Pierre

doi:10.1016/0092-8674(88)90552-1

Cited by 565 publications

(262 citation statements)

References 37 publications

Supporting

Mentioning

240

Contrasting

Unclassified

Order By: Relevance

“…Two independent activation functions, termed AF-1 and AF-2, have been identified in the ER. AF-1 is a ligand-independent activation region in the amino-terminal portion of the protein, whereas AF-2 is a ligand-dependent activation region in the carboxyl terminal ligand-binding domain (Webster et al 1988;Tora et al 1989;Danielian et al 1992;Tzukerman et al 1994). The available data suggest that an estrogen-induced conformational change in the ER promotes a synergistic interaction between AF-1 and AF-2 that leads to transcriptional activation (Beekman et al 1993;Kraus et al 1995).…”

mentioning

confidence: 87%

p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation

Kraus¹,

Kadonaga²

1998

Genes & Development

315

246

View full text Add to dashboard Cite

Estrogen-and antiestrogen-regulated, AF-2-dependent transcriptional activation by purified full-length human estrogen receptor (ER) was carried out with chromatin templates in vitro. With this system, the ability of purified human p300 to function as a transcriptional coactivator was examined. In the absence of ligand-activated ER, p300 was found to have little effect (less than twofold increase) on transcription, whereas, in contrast, p300 was observed to act synergistically with ligand-activated ER to enhance transcription. When transcription was limited to a single round, p300 and ER were found to enhance the efficiency of transcription initiation in a cooperative manner. On the other hand, when transcription reinitiation was allowed to occur, ER, but not p300, was able to increase the number of rounds of transcription. These results suggest a two-stroke mechanism for transcriptional activation by ligand-activated ER and p300. In the first stroke, ER and p300 function cooperatively to increase the efficiency of productive transcription initiation. In the second stroke, ER promotes the reassembly of the transcription preinitiation complex. Therefore, ER exhibits distinct, dual functions in transcription initiation and reinitiation.

show abstract

mentioning

confidence: 87%

p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation

Kraus¹,

Kadonaga²

1998

Genes & Development

315

246

View full text Add to dashboard Cite

show abstract

“…Positive clones were identified by loss of XbaI and NcoI restriction sites and confirmed using dideoxy sequencing (Sambrook et al, 1989). The reporter plasmid, 17M-ERE-globin-CAT, and the expression vectors, GAL-ER(HBD), have been described previously (Webster et al, 1988).…”

Section: Transfection Assaysmentioning

confidence: 99%

“…The synergistic activity of AF-1 and AF-2 can be examined using constructs in which AF-2 (region E) British Journal of Cancer (1997) (Webster et al, 1988;Tora et al, 1989a). In order to examine the mechanisms of trans-activation by HEAS further and to determine whether it trans-activates ERE-dependent gene expression in a similar way to HE1S, i.e.…”

Section: Transcriptional Activation By Hea5 In Mammalian Cellsmentioning

confidence: 99%

“…Functional studies have shown that region C encodes the DNA-binding domain (DBD) and region E contains the hormone-binding domain (HBD) Kumar et al, 1987). Regions A/B and E contain trans-activation functions 1 (AFI) and 2 (AF-2) respectively (Kumar et al, , 1987Webster et al, 1988;Lees et al, 1989;Tora et al, 1989a;Berry et al, 1990). Recent studies indicate that region F plays a role in modulating transcriptional activation by ER (Montano et al, 1995).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Presence of exon 5-deleted oestrogen receptor in human breast cancer: functional analysis and clinical significance

Desai

Luqmani²,

Walters³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

Summary A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described (Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malloy BW, McGuire WL 1991, Cancer Res 51: 105-1 09).We have examined the expression of the exon 5-deleted ER (HEA5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT -PCR). HEA5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% Cl, P=0.05). Presence of the HEA5 mRNA was associated with the presence of immunohistochemically detected ER (P=0.015) and progesterone receptor (PR) (P=0.02). There was a positive correlation between the presence of HEA5 and disease-free survival (P=0.05), suggesting that the presence of HEA5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HEA5. This antibody recognized the variant but not the wild-type ER protein. We show that HEA5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HEA5 in mammalian cells and showed that, in MCF-7 cells, HEA5 competes with wild-type ER to inhibit ERE-dependent trans-activation. Our results indicate that this variant is unlikely to be responsible for endocrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in regulating the expression of oestrogen-responsive genes in breast cancer.Keywords: breast neoplasm; exon; polymerase chain reaction; oestrogen receptor; transcription Two-thirds of human breast carcinomas are characterized by the presence of appreciable amounts of oestrogen receptor (ER) protein.A proportion of these tumours also contain progesterone receptor (PR) and it is generally accepted that ER regulates PR gene expression. The presence of ER is correlated with a better prognosis and ER+/PR+ tumours are much more likely to respond to endocrine therapy than ER-/PR-tumours. Interestingly, ER-/PR+ tumours are twice as likely to respond as ER+/PR-tumours. A significant proportion of ER+/PR+ tumours, however, fail to respond to endocrine therapy and those that do so eventually become resistant to such therapy. The mechanisms leading to endocrine resistance are not yet clear (for reviews see McGuire, 1978;McGuire et al, 1991;Fuqua, 1994;Horwitz, 1994;Sluyser, 1994).The human oestrogen receptor cDNA and its gene (Ponglikitmongkol et al, 1988) have been cloned and the molecular mechanisms by which it acts are well understood. Alignment of the predicted ER amino acid sequences from different species shows that it can be divided into six regions A to F on the basis of differing amino acid sequence homology . Functional studies have shown that region C encodes the DNA- Kumar et al, 1987). Regions A/B and E contain trans-activation functions 1 (AFI) and 2 (AF-2) respectively (Kumar et al, , 1987Webster et al, 1988; Lees et al, 1989; Tora et al, 1989a;Berry et ...

show abstract

“…GR is capable of both activating (8,9) and repressing (10-12) transcription. To activate transcription, GR's DNA-binding domain (DBD) cooperatively dimerizes on inverted repeat activating glucocorticoid response elements, or (+)GREs (Fig.…”

mentioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

show abstract

The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function

Cited by 565 publications

References 37 publications

p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation

p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation

Presence of exon 5-deleted oestrogen receptor in human breast cancer: functional analysis and clinical significance

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Contact Info

Product

Resources

About