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

Carascossa, Sophie; Dudek, Peter; Cenni, Bruno; Briand, Pierre-André; Picard, Didier

doi:10.1101/gad.568410

Cited by 88 publications

(98 citation statements)

References 62 publications

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“…Although we observed the labile O-GlcNAc modification on CARM1, no H 3 PO 4 (98 Da) shift was observed even in the presence of phosphatase inhibitor cocktails, suggesting that phosphorylated CARM1 is below the limit of detection (<5 %) by top-down MS. This result agrees with previous reports that CARM1 phosphorylation occurs mainly in mitosis [50,51,57] or in response to specific stimuli [52] in the central domain and implies that phosphorylation is unlikely to play a significant role in modulating CARM1 O-GlcNAcylation.…”

Section: O-glcnacylation Fine-tunes Carm1 Function By Regulating Subssupporting

confidence: 83%

“…Among the three phosphorylation events on CARM1, two occur in the central catalytic domain, mutation of which abrogates ERα-mediated transcription [50,51]. Phosphorylation at the third site Ser 448 enables CARM1 to directly interact with un-liganded ERα [52]. This direct interaction is important for ligandindependent activation of ERα and possibly contributes to tamoxifen resistance.…”

Section: O-glcnacylation Fine-tunes Carm1 Function By Regulating Subsmentioning

confidence: 99%

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O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

Charoensuksai

Kühn

Wang

et al. 2015

Biochemical Journal

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Co-activator-associated arginine methyltransferase 1 (CARM1) asymmetrically di-methylates proteins on arginine residues. CARM1 was previously known to be modified through O-linked-β-N-acetylglucosaminidation (O-GlcNAcylation). However, the site(s) of O-GlcNAcylation were not mapped and the effects of O-GlcNAcylation on biological functions of CARM1 were undetermined. In the present study, we describe the comprehensive mapping of CARM1 post-translational modification (PTM) using top-down MS. We found that all detectable recombinant CARM1 expressed in human embryonic kidney (HEK293T) cells is automethylated as we previously reported and that about 50% of this automethylated CARM1 contains a single O-linked-β-N-acetylglucosamine (O-GlcNAc) moiety [31]. The O-GlcNAc moiety was mapped by MS to four possible sites (Ser595, Ser598, Thr601 and Thr603) in the C-terminus of CARM1. Mutation of all four sites [CARM1 quadruple mutant (CARM1QM)] markedly decreased O-GlcNAcylation, but did not affect protein stability, dimerization or cellular localization of CARM1. Moreover, CARM1QM elicits similar co-activator activity as CARM1 wild-type (CARM1WT) on a few transcription factors known to be activated by CARM1. However, O-GlcNAc-depleted CARM1 generated by wheat germ agglutinin (WGA) enrichment, O-GlcNAcase (OGA) treatment and mutation of putative O-GlcNAcylation sites displays different substrate specificity from that of CARM1WT. Our findings suggest that O-GlcNAcylation of CARM1 at its C-terminus is an important determinant for CARM1 substrate specificity.

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Section: O-glcnacylation Fine-tunes Carm1 Function By Regulating Subssupporting

confidence: 83%

Section: O-glcnacylation Fine-tunes Carm1 Function By Regulating Subsmentioning

confidence: 99%

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

Charoensuksai

Kühn

Wang

et al. 2015

Biochemical Journal

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“…Nevertheless, the activation of ERa due to "crosstalk" with growth factors leads to ligand-independent ERa acivation, (34,35) resulting in failure in endocrine therapy. Taking into consideration that ligand-independent activation of ERa may define a path to endocrine resistance, enhanced mechanistic insight concerning the function of its ligand-independent regulator, such as PSAP, could identify novel prognostic markers of endocrine resistance and possible targets for therapeutic intervention in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

Sun

et al. 2012

Cancer Science

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Prosaposin, a secreted protein, is a well-known pleiotropic growth factor. Although a previous report has indicated that prosaposin is overexpressed in breast cancer cell lines, the role of prosaposin in the development of breast cancer remains to be identified. Here, we first revealed that prosaposin upregulated estrogen receptor alpha expression, nuclear translocation and transcriptional activity by western blot, immunofluorescence assay and dual luciferase reporter gene assay, respectively. Furthermore, we demonstrated prosaposin upregulated estrogen receptor alpha expression through MAPK-signaling pathway using MAPK inhibitor. Proliferation assay and tumor xenograft experiments in nude mice (n = 6 per group) further confirmed prosaposin could promote breast cancer growth significantly in vitro and in vivo. These findings suggested that prosaposin might enhance estrogen receptor alpha-mediated signaling axis and play a role in breast cancer development and progression. (Cancer Sci 2012; 103: 1820-1825 B reast cancer is the most common malignancy and the main cause of death from cancers in women.(1) The carcinogenesis of breast cancer is frequently hormone-dependent. The female sex-steroid hormone estrogen 17b-estradiol (E2) plays a prominent role in mediating the maturation, proliferation, differentiation, and influences the growth and development of breast cancer.(2) Numerous studies have indicated that E2 can induce and promote breast cancer and this process is mediated primarily by estrogen receptor alpha (ERa). (3)(4)(5) Estrogen receptor (ER) is a member of the steroid/nuclear receptor family of transcription regulators, while ERa is the predominant receptor isoform expressed in breast cancer. Approximately 70% of breast cancer patients score positive for ERa at diagnosis.(6-9) Estrogen receptor alpha promotes cell growth, metastasis and also mediates resistance to apoptosis or immunosurveillance in breast cancer. (10)(11)(12) Prosaposin (PSAP) exists as a secretory protein (70 kDa) as well as a lysosomal protein (65 kDa). The molecular weight difference depends on the post-translational glycosylation. (13) Lysosomal PSAP is the precursor of four sphingolipid activator proteins (saposin A-D) and is involved in hydrolysis of sphingolipids within lysosome.(14) Secretory PSAP is a well-known pleiotropic growth factor found in secretory body fluid, such as seminal plasma, bile, cerebrospinal fluid, human milk, (15,16) as well as neuronal surface membrane.(17) The distribution of PSAP suggests it may have some specific extracellular functions. PSAP-deficiency in human and mice is lethal. (18,19) Prosaposin knock-out mice also present with a series of developmental abnormalities in the nervous system and male reproductive organs. (18,20) Recent investigations show that PSAP could prevent cell death or apoptosis and promote cell survival. (21,22) Koochekpour et al. (23) focus on the function of PSAP in prostate cancer and find PSAP is overexpressed in prostate cancer, and also upregulates androgen receptor (...

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“…ERα's unique versatility as a sensor and an effector of molecular signaling make it an excellent candidate for this role. It is well known that structurally and functionally quite diverse molecules, such as steroids, peptide hormones, pollutants, ions, and amino acids, may regulate the transcriptional activity of ERα (19)(20)(21)(22), and that ERα transcriptional programs may be modulated in relation to the changes in levels of circulating hormones associated with each given reproductive stage (23,24). The nature of the signal perceived by ERα in fact imposes well-defined spatial conformations, enabling its interaction with the specific coregulators necessary for the selection of a precise gene network (25).…”

Section: Discussionmentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

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

117

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In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.energy metabolism | estrogen action | steroid hormone physiology | selective estrogen receptor modulators E strogen receptor (ER) α (or ESR1 or NR3A) is a transcription factor regulated by estrogens and nonestrogenic substances. ERα is highly expressed in reproductive organs and is indispensable for female reproductive functions (1). ERα is also present in most nonreproductive organs, where its role is currently object of intense investigation because of the large number of dysfunctions associated with the postmenopause and affecting the metabolic, cardiovascular, and immune systems (2-5).Application of the ER responsive element (ERE)-Luc reporter mouse, a transgenic mouse in which the luciferase reporter is driven by a promoter carrying multiple ERE copies (6), identified the liver as the organ in which ERs are most transcriptionally active (7,8). Further studies demonstrated that hepatic ERα transcriptional activity oscillates with the estrous cycle (tetradian oscillation) and is regulated by several compounds, including growth factors and nutritional proteins (9). This latter mechanism is instrumental for the synthesis of the circulating insulin-like growth factor 1 (IGF-1) necessary for the progression of the estrous cycle (9).These studies pointed to the hepatic ERα as a sensor of nutrient availability and a switch able to block the reproductive cycle in the event of malnutrition. On the other hand, a large body of evidence indicates that ERs are important regulators of several aspects of liver energy metabolism. Phenotypic analysis of mutant mice, including ERα (ERKO), ERβ, and aromatase KO mice, demonstrated that ERs play a pivotal role in the regulation of many processes related to the control of energy homeostasis, including energy expenditure, insulin sensitivity, and fat distribution (1, 10-13). In addition, investigation of the genetic programs controlled by hepatic ERs performed by comparing the transcriptomes of vehicle-and 17β-estradiol (E 2 )-treated ovariectomized (ovx) mice (14) established the potential for ER to recognize and regulate the transcription of numerous genes in...

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

Cited by 88 publications

References 62 publications

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

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