Ubiquitination of the Rat Uterine Estrogen Receptor: Dependence on Estradiol

Nirmala, P; Thampan, Raghava Varman

doi:10.1006/bbrc.1995.2093

Cited by 85 publications

(61 citation statements)

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“…It is well documented that ubiquitin E3 ligases function as transcriptional co-repressors with many transcription factors such as p53 (29), MAT␣2 (30), c-Myc (31), c-Jun (32), c-Fos (33,34), estrogen receptor (35), progesterone receptor (36), signal transducers and activators of transcription 1 (37), nuclear factor B (38,39), and SMAD1 (40), and they modulate these factors through a variety of mechanisms. For example, c-Jun and c-Fos undergo rapid degradation mediated by ubiquitination of lysine-rich domains within the protein (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Lung Krüppel-like Factor Contains an Autoinhibitory Domain That Regulates Its Transcriptional Activation by Binding WWP1, an E3 Ubiquitin Ligase

Conkright

Wani

Lingrel

2001

Journal of Biological Chemistry

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Lung Krü ppel-like factor (LKLF/Krü ppel-like factor 2), a member of the Krü ppel-like factor family of transcription factors, is expressed predominately in the lungs, with low levels of expression in other organs such as heart, spleen, skeletal muscle, and testis. LKLF is essential during pulmonary development and singlepositive T-cell development and is indispensable during mouse embryogenesis. In this study, we performed a series of experiments to define the activation domain of LKLF as a means to further advance the understanding of the molecular mechanisms underlying transcriptional regulation by this transcription factor. Using deletion analysis, it is shown that LKLF contains a transcriptional activation domain as well as a strong autoinhibitory subdomain. The inhibitory subdomain is able to independently suppress transcriptional activation of other strong activators such as viral protein 16, VP16. This occurs either when the inhibitory domain is fused directly to VP16 or when the inhibitory domain is independently bound to DNA by GAL4 DNA-binding domain independent of the VP16 activator. Overexpression of the LKLF autoinhibitory domain alone potentiates transactivation by wild type LKLF, suggesting that the inhibitory domain binds a cofactor that prevents LKLF from transactivating. A yeast-two hybrid screen identified WWP1, an E3 ubiquitin ligase that binds specifically to the LKLF inhibitory domain but not to other transcription factors. In mammalian cells, WWP1 functions as a cofactor by binding LKLF and suppressing transactivation. These data demonstrate that LKLF contains multiple domains that either potentiate or inhibit the ability of this factor to function as an activator of transcription; moreover, regulation of LKLF transactivation is attenuated by an E3 ubiquitin ligase, WWP1.

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Section: Discussionmentioning

confidence: 99%

Lung Krüppel-like Factor Contains an Autoinhibitory Domain That Regulates Its Transcriptional Activation by Binding WWP1, an E3 Ubiquitin Ligase

Conkright

Wani

Lingrel

2001

Journal of Biological Chemistry

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“…Phosphorylation (for review, see Ref. 15) and ubiquitinylation (15)(16)(17)(18)(19)(20) have been shown to regulate their functions and stability. Recently a new covalent modification of proteins and especially of transcriptional regulators have been described: SUMO-1 has been found to be conjugated to a growing list of proteins: the Ran GTPaseactivating protein RanGAP1 (21)(22)(23)(24), the NFB inhibitor IB␣ (25), the promyelocytic leukemia protein PML (26 -29), the nuclear dot protein Sp100 (27), the homeodomain-interacting protein kinase 2 HIPK2 (30), the topoisomerases I and II (31)(32), the tumor suppressor protein p53, and the protooncogene c-Jun (33)(34)(35).…”

Section: The Progesterone Receptor (Pr)mentioning

confidence: 99%

Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1

Chauchereau

Amazit

Quesne

et al. 2003

Journal of Biological Chemistry

131

119

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SUMO-1 (small ubiquitin-like modifier) conjugation regulates the subcellular localization, stability, and activity of a variety of proteins. We show here that SUMO-1 overexpression markedly enhances progesterone receptor (PR)-mediated gene transcription. PR undergoes a sumoylation at lysine 388 located in its N-terminal domain. However, sumoylation of the receptor is not responsible for enhanced transcription because substitution of its target lysine did not abolish the effect of SUMO-1 and even converted the receptor into a slightly more active transactivator. Furthermore estrogen receptor ␣ (ER␣)-driven transcription is also enhanced by SUMO-1 overexpression contrasting with the absence of sumoylation of this receptor. We thus analyzed SUMO-1 conjugation to the steroid receptor coactivator SRC-1. We showed that this protein contains two major sites of conjugation at Lys-732 and Lys- The progesterone receptor (PR) 1 is a transcription factor belonging to the superfamily of nuclear receptors. It contains two domains involved in transcription activation: the constitutive activation function 1 (AF-1) localized in the N-terminal region of the protein and the ligand-regulated activation function 2 (AF-2) corresponding to the ligand binding domain. X-ray diffraction analysis of receptor crystals have allowed a detailed study of the molecular mechanisms involved in ligand-induced conformational changes of the AF-2 region (1-9).To activate transcription, steroid hormone receptors recruit coactivators among which the p160 family seems to be of special importance. This family comprises SRC-1/NCoA-1 (steroid receptor coactivactor-1), SRC-2/TIF2/GRIP1 and SRC-3/ TRAM-1/ACTR/AIB1/RAC3/pCIP (for reviews, see Refs. 10 -11). CREB-binding protein (CBP) and p300 interact with both the nuclear receptors and the coactivators. Recruitment of histone acetylases allows local decondensation of chromatin thus facilitating transcription (for reviews, see .Aside from their regulation by specific ligands, nuclear receptors and especially steroid hormone receptors are known to undergo covalent modifications. Phosphorylation (for review, see have been shown to regulate their functions and stability. Recently a new covalent modification of proteins and especially of transcriptional regulators have been described: SUMO-1 has been found to be conjugated to a growing list of proteins: the Ran GTPaseactivating protein RanGAP1 (21-24), the NFB inhibitor IB␣ (25), the promyelocytic leukemia protein PML (26 -29), the nuclear dot protein Sp100 (27), the homeodomain-interacting protein kinase 2 HIPK2 (30), the topoisomerases I and II (31-32), the tumor suppressor protein p53, and the protooncogene c-Jun (33-35).SUMO-1 is a protein of 101 amino acids that has a low (18%) but significant homology to ubiquitin. Modification by SUMO-1 (sumoylation) has a marked similarity with ubiquitin conjugation reactions (for reviews, see Refs. 36 -37). It requires an E1-activating enzyme (SAE1/SAE2 in mammals, Aos1/Uba2 in yeast) and the E2-conjugating enzyme Ubc...

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“…Furthermore, it is possible that TCDD treatment affects the stability of the HES-1 protein by an as-yet unidentified pathway. HES-1 protein is degraded by the ubiquitin-proteasome pathway (Hirata et al, 2002), and this pathway is also involved in E 2 -induced down-regulation of the estrogen receptor (Nirmala and Thampan, 1995). Interestingly, the insulin receptor substrates 1 and 2, which are also degraded by the ubiquitinproteasome pathway, are up-regulated by treatment with E 2 (Morelli et al, 2003), suggesting that the ubiquitination levels of proteins can be both up-and down-regulated by E 2 depending on the target protein.…”

Section: Hes-1 Is Regulated By Tcdd 169mentioning

confidence: 99%

HES-1, a Novel Target Gene for the Aryl Hydrocarbon Receptor

et al. 2004

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Known mainly for its role as a toxin sensor, the aryl hydrocarbon receptor (AhR) complex is also involved in homeostasis regulation and differentiation processes and activated by xenobiotic compounds like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hairy and Enhancer of Split homolog-1 (HES-1) is a key regulator not only in differentiation, but also in the cell cycle, and we show here that HES-1 is a new target gene for AhR regulation. HES-1 is up-regulated by TCDD both at protein and mRNA levels in T47D human mammary carcinoma cells. Actinomycin D experiments have shown that the AhR-mediated up-regulation of HES-1 mRNA is caused by transcriptional activation of the HES-1 gene, and we have identified a functional AhR response element (XRE) at Ϫ48/Ϫ42 in the upstream regulatory region of human HES-1. The HES-1 protein downregulates expression of its own gene, and the HES element overlaps the XRE. Our data indicate that HES-1 and the AhR complex compete for binding to the composite HES/XRE element. Also, we have previously shown that HES-1 is downregulated by the estrogen receptor ligand 17␤-estradiol (E 2 ). Up-regulation of HES-1 expression is correlated with suppression of cell proliferation, and the E 2 -mediated down-regulation of HES-1 therefore increases cell proliferation. It is known that TCDD exerts antiestrogenic action in breast tissue both in vivo and in vitro. Our observation that both the estrogen receptor and AhR signaling pathways regulate HES-1, but with opposing effects, suggests the existence of a new pathway by which AhR represses E 2 -signaling.The balance between cell proliferation and cell differentiation affects cell fate; therefore, the proteins involved in these key biological processes must be tightly regulated. Many of the transcription factors involved constitute an intricate network of proteins belonging to the basic helix-loophelix (bHLH) superfamily of DNA binding transcription factors. The Hairy and Enhancer of Split homolog-1 (HES-1) is known to play a role in neuronal differentiation (Kageyama and Nakanishi, 1997) and belongs to the family of bHLH transcriptional repressors related to the Drosophila melanogaster Hairy and Enhancer of Split proteins. HES-1 also inhibits cell proliferation in neuronal cells (Castella et al

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Ubiquitination of the Rat Uterine Estrogen Receptor: Dependence on Estradiol

Cited by 85 publications

References 0 publications

Lung Krüppel-like Factor Contains an Autoinhibitory Domain That Regulates Its Transcriptional Activation by Binding WWP1, an E3 Ubiquitin Ligase

Lung Krüppel-like Factor Contains an Autoinhibitory Domain That Regulates Its Transcriptional Activation by Binding WWP1, an E3 Ubiquitin Ligase

Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1

HES-1, a Novel Target Gene for the Aryl Hydrocarbon Receptor

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