Phosphorylation of a Conserved Serine in the Deoxyribonucleic Acid Binding Domain of Nuclear Receptors Alters Intracellular Localization
| Autor: | Frances M. Sladek, Vladimir Parpura, Yann Brelivet, Vedrana Montana, Bryce M. Paschal, Kai Sun, Karthikeyani Chellappa, Yutaka Maeda, Dino Moras |
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| Přispěvatelé: | Laboratoire de Réactivité de Surface (LRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Mathematics (Department of Mathematics), Department of Mathematics of Keio University (Department of Mathematics of Keio University) |
| Rok vydání: | 2007 |
| Předmět: |
Cytoplasm
Amino Acid Motifs Receptors Cytoplasmic and Nuclear MESH: Amino Acid Sequence MESH: Down-Regulation MESH: Amino Acid Motifs MESH: Protein Structure Tertiary Transactivation Endocrinology Serine MESH: Animals Phosphorylation Conserved Sequence Protein Kinase C 0303 health sciences MESH: Conserved Sequence 030302 biochemistry & molecular biology MESH: DNA General Medicine Hepatocyte Nuclear Factor 4 Biochemistry Tetradecanoylphorbol Acetate MESH: Hepatocyte Nuclear Factor 4 Binding domain MESH: Cell Nucleus Transcriptional Activation MESH: Mutation MESH: Cell Line Tumor MESH: Rats Molecular Sequence Data Down-Regulation MESH: Receptors Cytoplasmic and Nuclear Biology 03 medical and health sciences Cell Line Tumor Animals Humans MESH: Serine Amino Acid Sequence Molecular Biology Transcription factor MESH: Tetradecanoylphorbol Acetate Protein kinase C 030304 developmental biology Cell Nucleus Serine/threonine-specific protein kinase MESH: Humans MESH: Molecular Sequence Data MESH: Phosphorylation MESH: Cytoplasm [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology DNA DNA-binding domain MESH: Protein Kinase C Protein Structure Tertiary Rats Nuclear receptor MESH: Trans-Activation (Genetics) Mutation Nuclear localization sequence |
| Zdroj: | Molecular Endocrinology-Baltimore Molecular Endocrinology-Baltimore-, Endocrine Society, 2007, 21 (6), pp.1297-311. ⟨10.1210/me.2006-0300⟩ Molecular Endocrinology-Baltimore-, 2007, 21 (6), pp.1297-311. ⟨10.1210/me.2006-0300⟩ |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2006-0300 |
| Popis: | Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4α (HNF4α). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4α and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4α (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4α as well as decreased endogenous HNF4α protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor α, retinoid X receptor α, and thyroid hormone receptor β) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor α and peroxisome proliferator-activated receptor α. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs. |
| Databáze: | OpenAIRE |
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