title: p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors.
abstract: In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses.
authors: Global Center of Excellence (GCOE) Program, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, The University of Tokyo, Japan.
authors: Yusuke
authors: Y
authors: Sekine
authors: Shuichi
authors: S
authors: Takagahara
authors: Ryo
authors: R
authors: Hatanaka
authors: Takeshi
authors: T
authors: Watanabe
authors: Haruka
authors: H
authors: Oguchi
authors: Takuya
authors: T
authors: Noguchi
authors: Isao
authors: I
authors: Naguro
authors: Kazuto
authors: K
authors: Kobayashi
authors: Makoto
authors: M
authors: Tsunoda
authors: Takashi
authors: T
authors: Funatsu
authors: Hiroshi
authors: H
authors: Nomura
authors: Takeshi
authors: T
authors: Toyoda
authors: Norio
authors: N
authors: Matsuki
authors: Erina
authors: E
authors: Kuranaga
authors: Masayuki
authors: M
authors: Miura
authors: Kohsuke
authors: K
authors: Takeda
authors: Hidenori
authors: H
authors: Ichijo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004296:Dopa Decarboxylase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D004330:Drosophila; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D048051:p38 Mitogen-Activated Protein Kinases; D004296:Dopa Decarboxylase; D004298:Dopamine