The Inhibitory Function in Human Progesterone Receptor N Termini Binds SUMO-1 Protein to Regulate Autoinhibition and Transrepression

Abdel-Hafiz, Hany A.; Takimoto, Glenn S.; Tung, Lin; Horwitz, Kathryn B.

doi:10.1074/jbc.m204573200

Cited by 135 publications

(132 citation statements)

References 48 publications

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“…2B). Furthermore, the non-sumoylated mutant was more active than the wild-type receptor, in agreement with the recent data of Abdel-Hafiz et al (48). These observations suggested that sumoylation of PR could not explain the overall effect of SUMO-1 on receptor-mediated gene Fig.…”

Section: Figsupporting

confidence: 82%

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

Chauchereau

Amazit

Quesne

et al. 2003

Journal of Biological Chemistry

129

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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Section: Figsupporting

confidence: 82%

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

Chauchereau

Amazit

Quesne

et al. 2003

Journal of Biological Chemistry

129

119

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“…1A). Consistent with previous reports (5,9), wt PR-B, but not K388R PR-B, was sumoylated in the presence of exogenous SUMO-1, and PR sumoylation was increased in response to progestin (lane 4). Notably, we detected partial sumoylation of wt PR-B, but not K388R, in the absence of ligand (lane 3) indicating that this modification occurs in unstimulated (serum starved) cells.…”

Section: Sumoylation Of Pr Represses Basal Proliferation In Breast Casupporting

confidence: 80%

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

Daniel

Lange

2009

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

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In advanced breast tumors, protein kinases are upregulated and steroid hormone receptors often function independently of ligand. Herein, we explored mechanisms of ligand-independent progesterone receptor (PR) activity. We showed previously that growth factorinduced phosphorylation of PR Ser-294 blocks PR Lys-388 sumoylation. SUMO-deficient mutant PR-B (K388R) thus provides a model receptor for the study of PR function in the context of high kinase activities. T47D cells stably expressing K388R PR-B exhibited increased ligand-independent proliferation and growth in soft agar relative to cells expressing wt PR-B or phospho-mutant (sumoylated) S294A PR-B. Expression of selected PR target genes (HB-EGF, IRS-1, and STC1) was significantly elevated in cells containing desumoylated (K388R) PR-B. Basal PR transcriptional activity occurred independently of progestins, was increased by activated CDK2, and attenuated by RU486. Notably, ChIP assays demonstrated that K388R PR-B and SRC1 were constitutively recruited to the STC1 promoter in the absence of progestin; PR Lys-388 sumoylation was required for HDAC3 recruitment. Knock-down of STC1 inhibited proliferation of cells expressing K388R PR-B. These data suggest a mechanism whereby phosphorylated, and thus desumoylated, PRs mediate increased expression of growth promoting genes. Our data explain why breast cancer models often remain insensitive to progestins, but are growth-inhibited by antiprogestins, and underscore the need to target PR-B and associated kinase activities as part of breast cancer therapy.HDAC ͉ phosphorylation ͉ sumoylation P rogesterone receptors (PR) mediate lobulo-alveolar proliferation during breast development and contribute to breast cancer progression, in part by synergizing with peptide growth factors (1-3). Regulation of PR activity occurs via the integration of ligand activated rapid signaling events and transcriptional activation (4). Peptide growth factors diminish the requirement for steroid hormone ligands by activation of protein kinases that directly target PR and its co-activators (i.e., a function of rapid signaling events). For example, direct phosphorylation of PR by MAPK or CDK2 alters transcriptional activity in part by modulating other posttranslational modifications including ubiquitination and sumoylation (3,5). Crosstalk between growth factor pathways and steroid receptors provides an exquisite mechanism for mammary epithelial cells to sense a dynamic range of hormone concentrations and selectively regulate specific promoters.Sumoylation of steroid hormone receptors represses transcriptional activity (6). We showed that EGF and protein kinasedependent (MAPK, CDK2) phosphorylation of PR-B on Ser-294 blocks sumoylation of PR Lys-388 (5). Undersumoylated receptors respond to low concentrations of ligand and are transcriptionally hyperactive at a subset of PRE (progesterone response element) containing target genes (HB-EGF). Sumoylation of PR is thus a key modulator of both the progesterone/PR dose-response curve and PR target gene ...

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“…Upon binding of their respective ligands, the receptors form homodimers at distinct hormone response elements in the promoter region of their target genes. AR, GR and PR were shown to undergo SUMOylation within a domain that functions as a transcriptional inhibitory domain (Poukka et al, 2000;Abdel-Hafiz et al, 2002;Tian et al, 2002). Substituting the SUMO-attachment residues within this domain enhances the transactivation potential of the receptors, again inferring an inhibitory role of SUMO in nuclear receptor signalling.…”

Section: Steroid Hormone Signallingmentioning

confidence: 99%

SUMO: a regulator of gene expression and genome integrity

2004

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Post-translational modification with the ubiquitin-like SUMO protein is involved in the regulation of many cellular key processes. The SUMO system modulates signal transduction pathways, including cytokine, Wnt, growth factor and steroid hormone signalling. SUMO frequently restrains the activity of downstream transcription factors in these pathways presumably by facilitating the recruitment of corepressors or mediating the assembly of repressor complexes. Additionally, evidence is accumulating that SUMO controls pathways important for the surveillance of genome integrity. SUMO regulates the PML/p53 tumour suppressor network, a key determinant in the cellular response to DNA damage. Moreover, proteins that maintain genomic stability by functioning at the interface between DNA replication, recombination and repair processes undergo SUMOylation. We will discuss some key findings that exemplify the role of SUMO in transcriptional regulation and genome surveillance.

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The Inhibitory Function in Human Progesterone Receptor N Termini Binds SUMO-1 Protein to Regulate Autoinhibition and Transrepression

Abstract: Although most studies of progesterone receptors (PR) and their two isoforms, PR-

Cited by 135 publications

References 48 publications

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

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

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

SUMO: a regulator of gene expression and genome integrity

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