title: Neurokinin B induces c-fos transcription via protein kinase C and activation of serum response factor and Elk-1 in immortalized GnRH neurons.
abstract: Mutations in neurokinin B (NKB) and its receptor, NK3R, were identified in human patients with hypogonadotropic hypogonadism, a disorder characterized by lack of puberty and infertility. Further studies have suggested that NKB acts at the level of the hypothalamus to control GnRH neuron activity, either directly or indirectly. We recently reported that treatment with senktide, a NK3R agonist, induced GnRH secretion and expression of c-fos mRNA in GT1-7 cells. Here, we map the responsive region in the murine c-fos promoter to between -400 and -200 bp, identify the signal transducer and activator of transcription (STAT) (-345) and serum response element (-310) sites as required for induction, a modulatory role for the Ets site (-318), and show that induction is protein kinase C dependent. Using gel shift and Gal4 assays, we further show that phosphorylation of Elk-1 leads to binding to DNA in complex with serum response factor at serum response element and Ets sites within the c-fos promoter. Thus, we determine molecular mechanisms involved in NKB regulation of c-fos induction, which may play a role in modulation of GnRH neuron activation.
authors: Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674.
authors: Christine A
authors: CA
authors: Glidewell-Kenney
authors: Crystal
authors: C
authors: Trang
authors: Paul P
authors: PP
authors: Shao
authors: Navarre
authors: N
authors: Gutierrez-Reed
authors: Adaku M
authors: AM
authors: Uzo-Okereke
authors: Djurdjica
authors: D
authors: Coss
authors: Pamela L
authors: PL
authors: Mellon
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D051379:Mice; D015287:Neurokinin B / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000502:physiology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D050807:ets-Domain Protein Elk-1; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B; D011493:Protein Kinase C