Daniel Metzger
University of Strasbourg
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Featured researches published by Daniel Metzger.
Science | 1995
Shigeaki Kato; Hideki Endoh; Yoshikazu Masuhiro; Takuya Kitamoto; Shimami Uchiyama; Haruna Sasaki; Shoichi Masushige; Yukiko Gotoh; Eisuke Nishida; Hiroyuki Kawashima; Daniel Metzger; Pierre Chambon
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
The EMBO Journal | 1990
M Berry; Daniel Metzger; Pierre Chambon
Various oestrogen responsive reporter genes and vectors expressing truncated or chimeric human oestrogen receptors (hER) containing either of the two independent hER transcriptional activation functions (TAF‐1 and TAF‐2) have been transfected into HeLa cells, chicken embryo fibroblast (CEF) or yeast cells to investigate the agonistic activity of the anti‐oestrogen 4‐hydroxytamoxifen (OHT). We demonstrate that the agonistic effect of OHT on the whole hER is due to the cell‐type and promoter‐context dependent activity of TAF‐1. In similar experiments, we show that the anti‐oestrogen, ICI 164,384, does not exhibit any oestrogenic activity and, therefore, acts always as a pure antagonist, even though it does not inhibit the activity of the isolated TAF‐1. We also confirm that the wild type human oestrogen receptor has no ligand independent transcriptional activity. The implications of our results for the variable antagonist/agonist activity of anti‐oestrogens in vivo are discussed.
Molecular Cell | 2000
Scott Bultman; Tom Gebuhr; Della Yee; Christian La Mantia; Jackie Nicholson; Anita C. Gilliam; Filippo Randazzo; Daniel Metzger; Pierre Chambon; Gerald R. Crabtree; Terry Magnuson
Mammalian SWI/SNF complexes utilize either brahma (Brm) or brahma-related gene 1 (Brg1) catalytic subunits to remodel nucleosomes in an ATP-dependent manner. Brm was previously shown to be dispensable, suggesting that Brm and Brg1 are functionally redundant. To test this hypothesis, we have generated a Brg1 null mutation by gene targeting, and, surprisingly, homozygotes die during the periimplantation stage. Furthermore, blastocyst outgrowth studies indicate that neither the inner cell mass nor trophectoderm survives. However, experiments with other cell types demonstrate that Brg1 is not a general cell survival factor. In addition, Brg1 heterozygotes are predisposed to exencephaly and tumors. These results provide evidence that biochemically similar chromatin-remodeling complexes have dramatically different functions during mammalian development.
Cell | 2007
Takashi Nakamura; Yuuki Imai; Takahiro Matsumoto; Shingo Sato; Kazusane Takeuchi; Katsuhide Igarashi; Yoshifumi Harada; Yoshiaki Azuma; Andrée Krust; Yoko Yamamoto; Hiroshi Nishina; Shu Takeda; Hiroshi Takayanagi; Daniel Metzger; Jun Kanno; Kunio Takaoka; T. John Martin; Pierre Chambon; Shigeaki Kato
Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
Nature | 2008
Ilaria Malanchi; Héctor Peinado; Deepika Kassen; Thomas Hussenet; Daniel Metzger; Pierre Chambon; Marcel Huber; Daniel Hohl; Amparo Cano; Walter Birchmeier; Joerg Huelsken
Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells. Similarly, epithelial tumour maintenance relies on cancer stem cells (CSCs), which co-opt stem cell properties. For most tumours, the cellular origin of these CSCs and regulatory pathways essential for sustaining stemness have not been identified. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34. Here we identify a population of cells in early epidermal tumours characterized by phenotypic and functional similarities to normal bulge skin stem cells. This population contains CSCs, which are the only cells with tumour initiation properties. Transplants derived from these CSCs preserve the hierarchical organization of the primary tumour. We describe β-catenin signalling as being essential in sustaining the CSC phenotype. Ablation of the β-catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased β-catenin signalling in malignant human squamous cell carcinomas. Because Wnt/β-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs and consequently eradicate squamous cell carcinomas.
Journal of Cell Biology | 2001
Liliane Michalik; Béatrice Desvergne; Nguan Soon Tan; Sharmila Basu-Modak; Pascal Escher; Jennifer Rieusset; Jeffrey M. Peters; Gürkan Kaya; Frank J. Gonzalez; Jozsef Zakany; Daniel Metzger; Pierre Chambon; Denis Duboule; Walter Wahli
We show here that the α, β, and γ isotypes of peroxisome proliferator–activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARα and β expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARα, β, and γ mutant mice, we demonstrate that PPARα and β are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARα is mainly involved in the early inflammation phase of the healing, whereas PPARβ is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARβ mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARα and β in adult mouse epidermal repair.
The EMBO Journal | 1993
Simak Ali; Daniel Metzger; Jean-Marc Bornert; Pierre Chambon
Using a transient co‐transfection system, we show that the human oestrogen receptor (hER) becomes phosphorylated in the presence of oestradiol (E2) as well as in the presence of the anti‐oestrogens 4‐hydroxy‐tamoxifen (OHT) and ICI 164, 384 (ICI), although at lower efficiencies than with E2. There are multiple sites of phosphorylation in hER; using deletion and point mutants one of these sites has been mapped in the N‐terminal A/B region at serine 118. Mutation of this serine to alanine caused, in a number of cell types, a significant reduction in transcriptional activation by hER from reporter genes containing an oestrogen response element (ERE), but did not affect the DNA binding properties or nuclear localization of hER. Thus phosphorylation of serine 118 is important for the action of the transcription activation function 1 (AF‐1) located in the A/B region of the oestrogen receptor.
Molecular and Cellular Biology | 1999
Hideki Endoh; Kazunori Maruyama; Yoshikazu Masuhiro; Yoko Kobayashi; Masahide Goto; Hitoshi Tai; Junn Yanagisawa; Daniel Metzger; Seiichi Hashimoto; Shigeaki Kato
ABSTRACT The estrogen receptor (ER) regulates the expression of target genes in a ligand-dependent manner. The ligand-dependent activation function AF-2 of the ER is located in the ligand binding domain (LBD), while the N-terminal A/B domain (AF-1) functions in a ligand-independent manner when isolated from the LBD. AF-1 and AF-2 exhibit cell type and promoter context specificity. Furthermore, the AF-1 activity of the human ERα (hERα) is enhanced through phosphorylation of the Ser118 residue by mitogen-activated protein kinase (MAPK). From MCF-7 cells, we purified and cloned a 68-kDa protein (p68) which interacted with the A/B domain but not with the LBD of hERα. Phosphorylation of hERα Ser118 potentiated the interaction with p68. We demonstrate that p68 enhanced the activity of AF-1 but not AF-2 and the estrogen-induced as well as the anti-estrogen-induced transcriptional activity of the full-length ERα in a cell-type-specific manner. However, it did not potentiate AF-1 or AF-2 of ERβ, androgen receptor, retinoic acid receptor alpha, or mineralocorticoid receptor. We also show that the RNA helicase activity previously ascribed to p68 is dispensable for the ERα AF-1 coactivator activity and that p68 binds to CBP in vitro. Furthermore, the interaction region for p68 in the ERα A/B domain was essential for the full activity of hERα AF-1. Taken together, these findings show that p68 acts as a coactivator specific for the ERα AF-1 and strongly suggest that the interaction between p68 and the hERα A/B domain is regulated by MAPK-induced phosphorylation of Ser118.
The EMBO Journal | 1989
Laszlo Tora; Mullick A; Daniel Metzger; Ponglikitmongkol M; Park I; Pierre Chambon
We demonstrate here that the human oestrogen receptor (hER) cDNA clone pOR8 obtained from MCF‐7 cells contains an artefactual point mutation which results in the substitution of a valine for a glycine at amino acid position 400 (Gly‐400––Val‐400). This mutation in the hormone binding domain of the cloned hER destabilizes its structure and decreases its apparent affinity for oestradiol at 25 degrees C, but not at 4 degrees C, when compared with the wild‐type hER with a Gly‐400.
Journal of Experimental Medicine | 2005
Christel Rousseaux; Bruno Lefebvre; Laurent Dubuquoy; Philippe Lefebvre; Olivier Romano; Johan Auwerx; Daniel Metzger; Walter Wahli; Béatrice Desvergne; Gian Carlo Naccari; Philippe Chavatte; Amaury Farce; Philippe Bulois; Antoine Cortot; Jean-Frederic Colombel; Pierre Desreumaux
5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.