title: Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway.
abstract: Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Donyo
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Hollander
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Abramovitch
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Naftelberg
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel gilast@post.tau.ac.il.
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein; D004402:Dysautonomia, Familial / Q000188:drug therapy* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010718:Phosphatidylserines / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation; D035602:Transcriptional Elongation Factors; D050807:ets-Domain Protein Elk-1
chemical_list: C115163:CREB1 protein, human; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C494112:ELK1 protein, human; C114720:Elp1 protein, human; D010718:Phosphatidylserines; D035602:Transcriptional Elongation Factors; D050807:ets-Domain Protein Elk-1; D048049:Extracellular Signal-Regulated MAP Kinases