title: Hypusination of eukaryotic initiation factor 5A via cAMP-PKA-ERK1/2 pathway is required for ligand-induced downregulation of LH receptor mRNA expression in the ovary.
abstract: Luteinizing hormone receptor (LHR) mRNA expression in the ovary is regulated post-transcriptionally by an LH receptor mRNA binding protein (LRBP). Eukaryotic initiation factor 5A (EIF5A), identified as an LRBP-interacting protein plays a crucial role in LHR mRNA expression. In this study, we have demonstrated that during hCG-induced LHR downregulation, a significant upregulation of eIF5A mRNA expression and hypusination of eIF5A protein occurs in a time dependent manner. Pretreatment with H89, a specific inhibitor of PKA, and U0126, a specific inhibitor of ERK1/2 significantly inhibited both hCG-induced eIF5A mRNA expression and hypusination of eIF5A protein. Pretreatment with GC7, a specific inhibitor of eIF5A hypusination significantly abolished hCG-induced LRBP mRNA and protein expression. Furthermore, GC7 pretreatment significantly inhibited hCG-induced interaction of LRBP with LHR mRNA as assessed by RNA electrophoretic mobility gel shift assay (REMSA). GC7 treatment also reversed LHR mRNA downregulation. Taken together, these results suggest that hCG-induced LHR mRNA downregulation is mediated by cAMP-PKA-ERK1/2 signaling leading to activation of eIF5A hypusination.
authors.affiliation: Departments of Obstetrics/Gynecology and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0617, USA.
authors.forename: Thippeswamy
authors.initials: T
authors.lastname: Gulappa
authors.affiliation: Departments of Obstetrics/Gynecology and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0617, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Menon
authors.affiliation: Departments of Obstetrics/Gynecology and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0617, USA. Electronic address: kmjmenon@umich.edu.
authors.forename: K M J
authors.initials: KM
authors.lastname: Menon
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D007986:Luteinizing Hormone / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism*; D010448:Peptide Initiation Factors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011974:Receptors, LH / Q000096:biosynthesis*; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007986:Luteinizing Hormone; D008239:Lysine; D048052:Mitogen-Activated Protein Kinase 3; D010448:Peptide Initiation Factors; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011974:Receptors, LH; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C021796:mevalonate kinase
keywords: Hypusination; LH receptor; LRBP; cAMP/PKA/ERK1/2; eIF5A