title: 17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination.
abstract: Protein monoubiquitination (monoUbq) (i.e., the attachment of one single ubiquitin to the substrate) is a non-proteolytic reversible modification that controls protein functions. Among other proteins, the estrogen receptor α (ERα), which mediates the pleiotropic effects of the cognate hormone 17β-estradiol (E2), is a monoubiquitinated protein. Although it has been demonstrated that E2 rapidly reduces ERα monoUbq in breast cancer cells, the impact of monoUbq in the regulation of the ERα activities is poorly appreciated. Here, we show that mutation of the ERα monoUbq sites prevents the E2-induced ERα phosphorylation in the serine residue 118 (S118), reduces ERα transcriptional activity, and precludes the ERα-mediated extranuclear activation of signaling pathways (i.e., AKT activation) thus impeding the E2-induced cyclin D1 promoter activation and consequently cell proliferation. In addition, the interference with ERα monoUbq deregulates E2-induced association of ERα to the insulin like growth factor receptor (IGF-1-R). Altogether these data demonstrate an inherent role for monoUbq in ERα signaling and point to the physiological function of ERα monoUbq in the regulation of E2-induced cell proliferation.
authors.affiliation: Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, Rome, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: La Rosa
authors.forename: Valeria
authors.initials: V
authors.lastname: Pesiri
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
authors.forename: Filippo
authors.initials: F
authors.lastname: Acconcia
mesh_terms: D020816:Amino Acid Motifs; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008938:Mitosis; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense; D010590:Phalloidine / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D014158:Transcription, Genetic; D054875:Ubiquitination; D016596:Vinculin / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D020662:Guanine Nucleotide Exchange Factors; D050505:Mutant Proteins; C108382:RABGEF1 protein, human; D017451:Receptors, Somatomedin; D016596:Vinculin; D010590:Phalloidine; D004958:Estradiol; D008156:Luciferases; D051057:Proto-Oncogene Proteins c-akt