Cyclic, Proteasome-Mediated Turnover of Unliganded and Liganded ERα on Responsive Promoters Is an Integral Feature of Estrogen Signaling

Reid, George; Hübner, Michael R; Métivier, Raphaël; Brand, Heike; Denger, Stefanie; Manu, Dominique; Beaudouin, Joël; Ellenberg, Jan; Gannon, Frank

doi:10.1016/s1097-2765(03)00090-x

Cited by 677 publications

(693 citation statements)

References 44 publications

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“…Linkage between PR hyperactivity and PR turnover (Fig. 4B) suggests that such complexes likely contain ubiquitin E3 ligases, as has been shown for activated ER (45). We reported that both PR downregulation and PR transcriptional synergy in the presence of MEKK1 and progestins were similarly blocked by inhibitors of p42/p44 MAPKs (PD98059 or UO126), the 26S proteasome (lactacystin), or nuclear export (leptomycinB) (14,15).…”

Section: Functions Of Liganded Prsupporting

confidence: 66%

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

et al. 2007

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Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30 min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFα and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.

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Section: Functions Of Liganded Prsupporting

confidence: 66%

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

et al. 2007

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“…ChIP-seq experiments in MCF-7 cells have shown binding of ERα to a significant number of estrogen target sites after 1 h of ICI 182,780 treatment (Welboren et al . 2009); in contrast, association of ERα with DNA was not observed 3 h after addition of ICI 182,780 in another study (Reid et al . 2003), possibly due to receptor degradation.…”

Section: Impact Of Ae-induced Erα Conformation On Cofactor Recruitmenmentioning

confidence: 91%

“…2015 and refs within); some of these proteins are recruited to DNA and can act as ERα coactivators (Lonard et al . 2000, Reid et al . 2003).…”

Section: Role Of Post-translational Modifications Of Erα By Ubi-like mentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…The primary genomic sensor for many dietary and environmental (e.g. xenobiotic) factors is the nuclear receptor superfamily of ligand-activated transcription factors, which bind steroid hormones, vitamin micronutrients and macronutrients such as fatty acids, lipids and bile acids (26)(27)(28)(29) .…”

Section: The Complex Aetiology Of Cancermentioning

confidence: 99%

The vitamin D receptor in cancer

2008

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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics. The cancer burdenThe impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1 . 5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13 % of all deaths worldwide and for one in every four deaths in the UK and USA (1) . The impact is also economic; $280 · 10 9 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40 % (2,3) . Major risk factors for cancer DietRecently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the secondmost preventable cause of cancer (after smoking) (3) . This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. Highprofile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime (4)(5)(6) . The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E ...

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Cyclic, Proteasome-Mediated Turnover of Unliganded and Liganded ERα on Responsive Promoters Is an Integral Feature of Estrogen Signaling

Cited by 677 publications

References 44 publications

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

Antiestrogens: structure-activity relationships and use in breast cancer treatment

The vitamin D receptor in cancer

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