Interaction of Steroid Hormone Receptors with the Transcription Initiation Complex

Beato, Miguel; Sánchez-Pacheco, Aurora

doi:10.1210/edrv-17-6-587

Cited by 361 publications

(147 citation statements)

References 259 publications

(142 reference statements)

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“…Surprisingly, we found that Hr interacts with TR. Previously identified proteins that interact with TR have been shown to interact with multiple nuclear receptors (9,10,(14)(15)(16)(17)(18)(19)(20)(21). In contrast, of the retinoid and steroid receptors tested here, Hr interacts only with TR.…”

mentioning

confidence: 80%

“…Equally important is the finding that although Hr binds to TR, it does not appear to bind to RAR or to their common partner, RXR. Though many proteins that interact with nuclear hormone receptors have been identified, all have been shown to be widely expressed and to bind to multiple receptors (9,10). In contrast, hr is predominantly expressed in brain and skin (11,13), and Hr binds to only one (TR) of several steroid and retinoid receptors tested.…”

Section: Discussionmentioning

confidence: 99%

“…Thyroid hormone receptors (TR) act by binding to specific DNA sequences and subsequently activating or repressing the transcription of nearby genes in response to hormone binding (7,8). Several proteins that interact with TR and other nuclear hormone receptors, including both coactivators and corepressors, have been identified (9,10).…”

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confidence: 99%

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The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Thompson

Bottcher

1997

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

129

106

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Thyroid hormone is a critical mediator of central nervous system (CNS) development, acting through nuclear receptors to modulate the expression of specific genes. Transcription of the rat hairless (hr) gene is highly upregulated by thyroid hormone in the developing CNS; we show here that hr is directly induced by thyroid hormone. By identifying proteins that interact with the hr gene product (Hr), we find that Hr interacts directly and specifically with thyroid hormone receptor (TR)-the same protein that regulates its expression. Unlike previously described receptorinteracting factors, Hr associates with TR and not with retinoic acid receptors (RAR, RXR). Hr can act as a transcriptional repressor, suggesting that its interaction with TR is part of a novel autoregulatory mechanism.Many factors, both genetic and environmental, contribute to the formation and function of the mammalian central nervous system (CNS). An essential component of these processes is thyroid hormone (TH); if thyroid hormone levels are perturbed, abnormal development ensues, resulting in neurological deficits that include severe mental retardation (1-4). The effects of TH are mediated through the action of specific nuclear receptor proteins (5, 6). Thyroid hormone receptors (TR) act by binding to specific DNA sequences and subsequently activating or repressing the transcription of nearby genes in response to hormone binding (7,8). Several proteins that interact with TR and other nuclear hormone receptors, including both coactivators and corepressors, have been identified (9, 10).Although much is known about the mechanism of action of TR and other nuclear receptors, far less is known about the genes regulated by these receptors. We have shown that the rat hairless (hr) gene is highly up-regulated (Ͼ10-fold) by thyroid hormone in developing brain (11). The rapid induction (Ͻ4 hr) occurs even in the absence of protein synthesis, suggesting that hr is directly regulated by TR. Direct target genes are particularly important because such genes likely constitute the first step in the genetic program responsible for TH-mediated aspects of neural development. We show here that the upstream regulatory region of the hr gene includes a potent thyroid hormone response element (TRE), indicating that hr is indeed a direct target of TR.The murine hr locus was originally identified as a spontaneous mutation caused by an endogenous retrovirus (12). The hr gene is expressed predominantly in skin and brain; the mutant phenotype in skin is progressive hair loss and increased susceptibility to cancer, while the neurological phenotype has not yet been described (11, 13). The hr gene encodes a putative protein of approximately 127 kDa that lacks homology to known structural motifs other than a cluster of cysteine residues proposed to form a zinc finger (13). Toward defining the function of the hr gene product (Hr), we identified proteins that interact with Hr. Surprisingly, we found that Hr interacts with TR. Previously identified proteins that interact wit...

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confidence: 80%

Section: Discussionmentioning

confidence: 99%

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The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Thompson

Bottcher

1997

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

129

106

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“…Upon binding ligand, the receptor undergoes a conformational change, an event that leads to the displacement of heat-shock proteins, receptor dimerization, and subsequent interaction of ER␣ with specific estrogen response elements (EREs) located within the regulatory regions of target genes (6 -8). Depending on the cell and promoter context, the DNA-bound receptor can exert either a positive or negative effect on target gene transcription (9).…”

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confidence: 99%

Modulation of Estrogen Receptor-α Transcriptional Activity by the Coactivator PGC-1

Tcherepanova

Puigserver

Norris

et al. 2000

Journal of Biological Chemistry

201

160

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A transcriptional coactivator of the peroxisome proliferator-activated receptor-␥ (PPAR␥), PPAR␥-coactivator-1(PGC-1) interacts in a constitutive manner with the hinge domain of PPAR␥ and enhances its transcriptional activity. In this study we demonstrate that PGC-1 is a coactivator of estrogen receptor-␣ (ER␣)-dependent transcriptional activity. However the mechanism by which PGC-1 interacts with ER␣ is different from that of PPAR␥. Specifically, it was determined that the carboxyl terminus of PGC-1 interacts in a ligand-independent manner with the ER␣ hinge domain. In addition, an LXXLL motif within the amino terminus of PGC-1 was shown to interact in an agonist-dependent manner with the AF2 domain within the carboxyl terminus of ER␣. The ability of PGC-1 to associate with and potentiate the transcriptional activity of an ER␣-AF2 mutant that is unable to interact with the p160 class of coactivators suggests that this coactivator may have a unique role in estrogen signaling. It is concluded from these studies that PGC-1 is a bona fide ER␣ coactivator, which may serve as a convergence point between PPAR␥ and ER␣ signaling.

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“…The second but weaker activation function (AF-2) localizes to the ligand binding domain; it requires hormone for activation and perhaps also an intramolecular interaction with the AF-1 region (1-6). The apo-ligand binding domains of steroid receptors interact with transcriptional corepressors and heat-shock proteins, and the ligand-induced conformation in the ligand binding domain enables interactions between several coactivators and AF-2 (7)(8)(9)(10)(11)(12). The steroid receptor zinc finger region (ZFR) consists of two zinc finger (ZF) structures (13).…”

mentioning

confidence: 99%

Coregulator Small Nuclear RING Finger Protein (SNURF) Enhances Sp1- and Steroid Receptor-mediated Transcription by Different Mechanisms

Poukka¹,

Aarnisalo²,

Santti³

et al. 2000

Journal of Biological Chemistry

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The small nuclear RING finger protein SNURF is not only a coactivator in steroid receptor-dependent transcription but also activates transcription from steroidindependent promoters. In this work, we show that SNURF, via the RING finger domain, enhances protein binding to Sp1 elements/GC boxes and interacts and cooperates with Sp1 in transcriptional activation. The activation of androgen receptor (AR) function requires regions other than the RING finger of SNURF, and SNURF does not influence binding of AR to cognate DNA elements. The zinc finger region (ZFR) together with the hinge region of AR are sufficient for contacting SNURF. The nuclear localization signal in the boundary between ZFR and the hinge region participates in the association of AR with SNURF, and a receptor mutant lacking the C-terminal part of the bipartite nuclear localization signal shows attenuated response to coexpressed SNURF. Some AR ZFR point mutations observed in patients with partial androgen insensitivity syndrome or male breast cancer impair the interaction of AR with SNURF and also render AR refractory to the transcription-activating effect of SNURF. Collectively, SNURF modulates the transcriptional activities of androgen receptor and Sp1 via different domains, and it may act as a functional link between steroid-and Sp1-regulated transcription.The androgen receptor (AR), 1 a member of the steroid receptor family, acts as a hormone-regulated transcription factor. The N-terminal region contains a powerful ligand-independent transcription activation function-1 (AF-1). The second but weaker activation function (AF-2) localizes to the ligand binding domain; it requires hormone for activation and perhaps also an intramolecular interaction with the AF-1 region (1-6). The apo-ligand binding domains of steroid receptors interact with transcriptional corepressors and heat-shock proteins, and the ligand-induced conformation in the ligand binding domain enables interactions between several coactivators and AF-2 (7-12). The steroid receptor zinc finger region (ZFR) consists of two zinc finger (ZF) structures (13). The first ZF is responsible for contacting the specific hormone response element (HRE), whereas the second ZF stabilizes the receptor-DNA interactions and participates in homodimer formation (13-16). The bipartite nuclear localization signal (NLS) begins immediately C-terminal to the second ZF and continues through the first amino acid residues of the hinge region (17, 18). Besides binding to HREs and mediating the dimerization, the ZFRs of steroid receptors have also other less well characterized but nevertheless important functions. Unlike glucocorticoid receptor (GR) null mice, animals with a GR mutation that prevents dimerization and efficient DNA binding are viable, attesting to the importance in vivo of those GR activities that are independent of DNA binding (19). In human males, mutations in the AR ZFR can lead to either complete or partial androgen insensitivity syndrome (3,20,21). AR ZFR is important in transrepression of AP1-a...

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Interaction of Steroid Hormone Receptors with the Transcription Initiation Complex

Cited by 361 publications

References 259 publications

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Modulation of Estrogen Receptor-α Transcriptional Activity by the Coactivator PGC-1

Coregulator Small Nuclear RING Finger Protein (SNURF) Enhances Sp1- and Steroid Receptor-mediated Transcription by Different Mechanisms

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