title: Repression of the estrogen receptor-alpha transcriptional activity by the Rho/megakaryoblastic leukemia 1 signaling pathway.
abstract: Although involved in processes leading to the emergence and development of hormone-dependent breast cancers, the estrogen receptor alpha (ERalpha) also prevents transformed cells from progressing toward a more aggressive phenotype. The transcriptional activity of ERalpha is mediated through two transactivation functions, called activation function 1 and 2, whose respective involvement varies in a cell-specific manner. Here, we identify the Rho/megakaryoblastic leukemia 1 (MKL1) signaling pathway as a main actor in controlling the cell-specific activity of both transactivation functions of ERalpha. Notably, we show that, when the coregulator MKL1 is sequestered in an inactive form by unpolymerized actin, the transcriptional activity of ERalpha mainly relies on the activation function 1. The activation of MKL1, which results from its dissociation from unpolymerized actin, promoted by the ability of Rho to support polymeric actin accumulation, silences the activation function 1 of ERalpha and allows the receptor to mainly act through its activation function 2. Importantly, this switch in the respective contribution exerted by both transactivation functions is correlated with an impaired ability of ERalpha to efficiently transactivate estrogen-regulated reporter genes. MKL1 is further shown to be present on estrogen-responsive genes in vivo. Interestingly, the Rho/MKL1 signaling pathway is activated during the epithelial-mesenchymal transition. A reduced transactivation efficiency of ERalpha, resulting from the activation of this pathway, may therefore suppress the protective role exerted by ERalpha toward tumor progression and invasiveness.
authors.affiliation: Equipe Récepteurs des Estrogènes et Destinée Cellulaire, UMR CNRS 6026, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huet
authors.forename: Yohann
authors.initials: Y
authors.lastname: Mérot
authors.forename: Frédéric
authors.initials: F
authors.lastname: Percevault
authors.forename: Christophe
authors.initials: C
authors.lastname: Tiffoche
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Noureddine
authors.initials: N
authors.lastname: Boujrad
authors.forename: Farzad
authors.initials: F
authors.lastname: Pakdel
authors.forename: Raphaël
authors.initials: R
authors.lastname: Métivier
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
mesh_terms: D000199:Actins / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D015534:Trans-Activators; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000199:Actins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D004247:DNA; D020741:rho GTP-Binding Proteins