Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway

Human Molecular Genetics
Maya DonyoGil Ast

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, ou...Continue Reading

References

Mar 1, 1992·Molecular and Cellular Biology·R H ChenJ Blenis
Apr 1, 1996·Current Opinion in Cell Biology·R Treisman
Dec 9, 1997·Neuron·S FinkbeinerM E Greenberg
Feb 17, 2001·American Journal of Human Genetics·S A SlaugenhauptJ F Gusella
Feb 17, 2001·American Journal of Human Genetics·S L AndersonB Y Rubin
Nov 21, 2001·The Journal of Biological Chemistry·Nicola A HawkesJesper Q Svejstrup
Nov 21, 2001·Nature Reviews. Molecular Cell Biology·A D Sharrocks
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Jun 22, 2002·Current Opinion in Genetics & Development·Susan A Slaugenhaupt, James F Gusella
Oct 16, 2002·The Journal of Pediatrics·Felicia B AxelrodChanna Maayan
Feb 11, 2003·American Journal of Human Genetics·Math P CuajungcoSusan A Slaugenhaupt
Mar 1, 2003·Neurochemical Research·Rita MozziGianfrancesco Goracci
Jun 6, 2003·Biochemical and Biophysical Research Communications·Sylvia L AndersonBerish Y Rubin
Sep 16, 2003·Neuron·William Dauer, Serge Przedborski
Oct 28, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Luca Colucci-D'AmatoUmberto di Porzio
Feb 26, 2004·Muscle & Nerve·Felicia B Axelrod
Mar 16, 2004·The European Journal of Neuroscience·Limin MaoJohn Q Wang
Aug 30, 2005·Biochemical and Biophysical Research Communications·Sylvia L Anderson, Berish Y Rubin
May 10, 2006·Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society·Felicia B Axelrod
Jun 28, 2006·The Journal of Pharmacology and Experimental Therapeutics·Shougang Zhuang, Rick G Schnellmann
Nov 28, 2006·Biochimica Et Biophysica Acta·James A McCubreyRichard A Franklin
May 1, 2007·Current Opinion in Cell Biology·Jesper Q Svejstrup
Jul 31, 2007·International Journal of Toxicology·Gunjan GoelKlaus Becker
Jan 25, 2008·Nature Reviews. Molecular Cell Biology·Gerrit van MeerGerald W Feigenson
Mar 6, 2008·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·Susan StevensonM Julie Thornton
Nov 27, 2008·Pediatric Research·Gabrielle Gold-von SimsonFelicia B Axelrod

❮ Previous
Next ❯

Related Concepts

Related Feeds

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.