Cellular Mechanisms Which Distinguish between Hormone‐ and Antihormone‐Activated Estrogen Receptor

McDonnell, Donald P.; Dana, Sharon L.; Hoener, Patricia A.; Lieberman, Benjamin A.; Imhof, Markus O.; Stein, Robert B.

doi:10.1111/j.1749-6632.1995.tb31374.x

Cited by 63 publications

(46 citation statements)

References 43 publications

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“…Thus, TR mutants can achieve ligand-bound conformations that are intermediate between those of unliganded and T3-bound wild-type TR. This is similar to the effects of partial agonists and antagonists on steroid receptor function (27). The ability to uncouple T3 regulation of TR-RXR interaction from T3-dependent activation suggests the existence of multiple TR conformations that recruit specific cofactors with different functions.…”

Section: Discussionsupporting

confidence: 56%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

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Thyroid hormone receptor (TR) functions as part of multiprotein complexes that also include retinoid X receptor (RXR) and transcriptional coregulators. We have found that both the TR CoR box and ninth heptad are required for RXR interaction and in turn for interaction with corepressor proteins N-CoR and SMRT. Remarkably, the recruitment of RXR to repression-defective CoR box and ninth-heptad mutants via a heterologous dimerization interface restores both corepressor interaction and repression. The addition of thyroid hormone obviates the CoR box requirement for RXR interaction, provided that the AF2 activation helix at the C terminus of TR is intact. These results indicate that RXR differentially recognizes the unliganded and liganded conformations of TR and that these differences appear to play a major role in the recruitment of corepressors to TR-RXR heterodimers.Thyroid hormone receptor (TR) is a multifunctional protein. It is a transcriptional repressor in the absence of ligand and a transcriptional activator in the presence of thyroid hormone (T3). Repression is mediated by interaction with a family of corepressor proteins, including N-CoR and SMRT (10,17,34,45). A ligand-induced conformational change causes dissociation of the corepressor and recruitment of a transcriptional coactivator to the DNA-bound TR. TR binds DNA most effectively as a heterodimer with retinoid X receptor (RXR) (6,19,22,23,25,44,47). Although RXR itself is a retinoid receptor (24), its main function in TR action does not appear to require retinoid binding (14). The TR-RXR interaction is stable in solution in both the presence and absence of ligand, and it has previously been suggested that the primary role of RXR is to increase the affinity and specificity of TR for T3 response elements, which often consist of two TR half-sites separated by 4 bp (39).The primary region of importance for the TR-RXR interaction in solution is the region which is generally known as the ninth heptad, corresponding to helices 10 and 11 of the crystal structure of the TR ligand binding domain (LBD) (40). The importance of this domain explains why C-terminal deletions of TR and the C-terminal variant TR␣2 do not interact with RXR in solution (31, 42). Interestingly, although the interaction between TR and RXR is ligand independent, two groups have previously described TR ninth-heptad point mutants which interact with RXR only in the presence of T3 (1, 28). Although the TR LBD structure has been solved only in the presence of ligand, a comparison with the unliganded RXR suggests that one of the effects of ligand binding is conformational change in the region between helices 10 and 11 in addition to the turning back of the amphipathic AF2 helix (helix 12) towards the core of the TR (5, 40).In contrast to the importance of C-terminal domains for RXR interaction, previous studies of TR interaction with NCoR and SMRT have focused on the CoR box within the hinge region of TR (10, 17). Like the ninth heptad, the CoR box is highly conserved among receptors that int...

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Section: Discussionsupporting

confidence: 56%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

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“…Since tamoxifen can act as an estrogen agonist in the context of certain promoters (McDonnell et al, 1995b;Ramkumar and Adler, 1995), we further investigated this phenomenon. For these experiments, MCF-7 cells were cultured in serum free medium for 1 day prior to treatment.…”

Section: Resultsmentioning

confidence: 99%

BRCA1 expression is not directly responsive to estrogen

et al. 1997

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Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-b estradiol (E 2 ) in estrogen receptor containing breast cancer cell lines. Our previous studies have shown that BRCA1 transcription is also regulated with the cell cycle, reaching maximal levels just before the onset of DNA synthesis. In this study, we have examined whether the estrogen induction of BRCA1 is direct or is a result of the mitogenic activity of the hormone. Four lines of evidence lead us to conclude that E 2 induces BRCA1 primarily through an increase in DNA synthesis: (1) The kinetics and magnitude of induction are di erent from the directly E 2 inducible gene, pS2; (2) Induction of BRCA1, but not pS2, is blocked by cycloheximide indicating that de novo protein synthesis is required; (3) Other hormonal and growth factor treatments that induce DNA synthesis have a similar e ect, including IGF-1, EGF and DNA synthetic ares induced by tamoxifen and retinoic acid; (4) BRCA1 genomic fragments near the 5' end of the gene containing putative estrogen response elements fail to respond to E 2 when transfected into breast cancer cell lines. The most consistent explanation for these ®ndings and other published studies is that BRCA1 transcription is induced as a result of the mitogenic activity of E 2 in estrogen receptor positive cells.

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“…While activation by these factors occurs most efficiently in the presence of oestrogens, their promotion of AF-1 and AF-2 responses is certainly adequate for investigating transcription in the absence of the hormone. An emerging concept for steroid hormone receptors is therefore that they function not only as direct transducers of hormonal effects but, as members of the cellular nuclear transcription factor pool, also serve as key points of convergence for multiple signal trans-duction pathways (McDonnell et al 1995).…”

Section: Figurementioning

confidence: 99%

Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer.

Nicholson¹,

McClelland²,

Robertson³

et al. 1999

Endocrine-Related Cancer

143

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Multiple lines of evidence implicate steroid hormone and growth factor cross-talk as a modulator of endocrine response in breast cancer and that aberrations in growth factor signaling pathways are a common element in the endocrine resistant phenotype. Delineation of these relationships is thus an important diagnostic goal in cancer research, while the targeting of aberrant growth factor signaling Endocrine-Related Cancer (1999) 6 373-387 holds the promise of improving therapeutic response rates.

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Cellular Mechanisms Which Distinguish between Hormone‐ and Antihormone‐Activated Estrogen Receptor

Cited by 63 publications

References 43 publications

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

BRCA1 expression is not directly responsive to estrogen

Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer.

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