Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

Coleman, Kevin M.; Dutertre, Martin; El-Gharbawy, Abeer; Rowan, Brian G.; Weigel, Nancy L.; Smith, Carolyn L.

doi:10.1074/jbc.m212312200

Cited by 64 publications

(47 citation statements)

References 80 publications

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“…It had been shown that cAMP/PKA stimulates the recruitment of cyclin D1 to unliganded ERa (Lamb et al 2000) and of the coactivator SRC-1 to the unliganded chicken PR (Rowan et al 2000), but whether the latter is true for ERa and whether either cofactor is necessary for the response were not determined. In fact, a mutational analysis indicated that none of the known phosphorylation sites of SRC-1 is necessary (Coleman et al 2003).…”

Section: Discussionmentioning

confidence: 99%

“…This does not exclude that cAMP/PKA could modulate certain ERb target genes through alternate mechanisms. It was demonstrated that activation of ERb by cAMP/PKA could be monitored in transfections with reporter genes containing promoter-proximal cryptic AP1 sites (Coleman et al 2003), but it should be emphasized that all of our reporter genes were devoid of these. Our results suggest that cAMP signaling would help to discriminate, at least at certain target genes, between ERa and ERb effects in cells that coexpress the two isoforms, and thereby to fine-tune estrogenic responses.…”

Section: Carm1 Is the Link Between Pka And Eramentioning

confidence: 99%

“…They are substrates for a variety of kinases, and their post-translational modifications modify their coactivator activities. Although certain coactivators can potentiate ligand-independent activation of ERa (for example, see Zwijsen et al 1998;Coleman et al 2003;Fenne et al 2008; see also Rowan et al 2000), it has not been determined which one, if any, is necessary. Nevertheless, they have remained good candidates as mediators of ligand-independent pathways, including the activation of ERa by cAMP.…”

mentioning

confidence: 99%

“…In contrast, how cAMP functions to activate unliganded ERa has remained largely enigmatic. Early on, inhibitor studies already suggested that cAMP signals to ERa through protein kinase A (PKA) (Aronica and Katzenellenbogen 1993;see also Al-Dhaheri and Rowan 2007), and limited mutational analyses pointed to the HBD as the target domain (Smith et al 1993;Coleman et al 2003), rather than AF1, as for growth factors, or the hinge, as for cyclin D1. Whether the direct phosphorylation of ERa by PKA, which does indeed occur and modulates its activity (Aronica and Katzenellenbogen 1993;Chen et al 1999b;Cui et al 2004;Michalides et al 2004;Al-Dhaheri and Rowan 2007;Zwart et al 2007), plays any role has not been clarified.…”

mentioning

confidence: 99%

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CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Carascossa

Dudek²,

Cenni³

et al. 2010

Genes Dev.

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The estrogen receptor a (ERa) is activated as a transcription factor by both estrogen and a large variety of other extracellular signals. The mechanisms of this ligand-independent activation, notably by cAMP signaling, are still largely unknown. We now close the gap in the signaling pathway between cAMP and ERa. Whereas the direct phosphorylation of ERa by the cAMP-activated protein kinase A (PKA) is dispensable, the phosphorylation of the coactivator-associated arginine methyltransferase 1 (CARM1) by PKA at a single serine is necessary and sufficient for direct binding to the unliganded hormone-binding domain (HBD) of ERa, and the interaction is necessary for cAMP activation of ERa. Sustained PKA activity promoting a constitutive interaction may contribute to tamoxifen resistance of breast tumors. Binding and activation involve a novel regulatory groove of the ERa HBD. As a result, depending on the activating signal, ERa recruits different coactivator complexes to regulate alternate sets of target genes.[Keywords: Steroid receptor; signaling; coactivator; protein kinase A; breast cancer; endocrine resistance] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

Section: Carm1 Is the Link Between Pka And Eramentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Carascossa

Dudek²,

Cenni³

et al. 2010

Genes Dev.

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“…The expression plasmid for NCoR was provided by Dr M Bagchi (Zhang et al 1998). The expression plasmid for SMRT was provided by Dr B G Rowan (Coleman et al 2003). The expression plasmids for SRC-1 and SRA were provided by Dr B W O'Malley .…”

Section: Cell Culture Transient Transfection and Reporter Assaysmentioning

confidence: 99%

Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors α and β by coactivators and corepressors

Klinge¹,

Jernigan²,

Mattingly³

et al. 2004

Journal of Molecular Endocrinology

181

132

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One mechanism by which ligand-activated estrogen receptors and (ER and ER ) stimulate gene transcription is through direct ER interaction with specific DNA sequences, estrogen response elements (EREs). ERE-bound ER recruits coactivators that stimulate gene transcription. Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity, conformation, and transcriptional activity, indicating that the ERE sequence is an allosteric effector of ER action. Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors. CHO-K1 cells transfected with ER or ER show ERE sequence-dependent differences in the functional interaction of ER and ER with coactivators steroid receptor coativator 1 (SRC-1), SRC-2 (glucocorticoid receptor interacting protein 1 (GRIP1)), SRC-3 amplified in breast cancer 1 (AIB1) and ACTR, cyclic AMP binding protein (CBP), and steroid receptor RNA activator (SRA), corepressors nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone recpetors (SMRT), and secondary coactivators coactivator associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferase 1 (PRMT1). We note both ligand-independent as well estradiol-and 4-hydroxytamoxifen-dependent differences in ER-coregulator activity. In vitro ER-ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell-based results, substantiating the importance of the full-length proteins in regulating ER activity. These data demonstrated that the ERE sequence impacts estradioland 4-hydroxytamoxifen-occupied ER and ER interaction with coregulators as measured by transcriptional activity in mammalian cells.

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Steroid receptor phosphorylation: Assigning function to site‐specific phosphorylation

Ward

Weigel

2009

BioFactors

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Steroid receptors (SRs) are hormone-activated transcription factors important for a wide variety of cellular functions. Posttranslational modifications of SRs, including phosphorylation, ubiquitination, acetylation, and sumoylation regulate their expression and function. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases shown to modulate phosphorylation influence the integration between cell-signaling pathways and SR action. These phosphorylation sites have been identified in all of the functional domains with the majority being located within the amino-terminal portions of the receptors. The regulation of function is receptor specific, site specific, and often dependent on the cellular context. Numerous roles for site-specific phosphorylation have been elucidated including sensitivity of hormone response, DNA binding, expression, stability, subcellular localization, dimerization, and proteinprotein interactions that can determine the regulation of specific target genes. This review summarizes the current knowledge regarding receptor site-specific phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.

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Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

Cited by 64 publications

References 80 publications

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors α and β by coactivators and corepressors

Steroid receptor phosphorylation: Assigning function to site‐specific phosphorylation

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