TAILIEUCHUNG - Báo cáo Y học: Mitogen-activated protein kinase kinase negatively modulates ciliary neurotrophic factor-activated choline acetyltransferase gene expression

The expression of the choline acetyltransferase (ChAT) enzyme that synthesizes the neurotransmitter acetylcholine (ACh) is upregulated by ciliary neurotrophic factor (CNTF). We studied the involvement of the mitogen-activated protein kinase (MAPK) pathway in regulating ChAT expression in a murine septal cell line. Surprisingly, we found that PD98059 and U0126, two structurally distinct inhibitors of MAPK kinase (MEK1), increased both basal and CNTF-induced ACh production. | Eur. J. Biochem. 269 850-858 2002 FEBS 2002 Mitogen-activated protein kinase kinase negatively modulates ciliary neurotrophic factor-activated choline acetyltransferase gene expression Tiffany Mellott1 Ignacio Lopez-Coviella2 Jan Krzysztof Blusztajn1 2 and Brygida Berse1 1 Department of Pathology and Laboratory Medicine and department of Psychiatry Boston University School of Medicine Boston MA USA The expression of the choline acetyltransferase ChAT enzyme that synthesizes the neurotransmitter acetylcholine ACh is upregulated by ciliary neurotrophic factor CNTF . We studied the involvement of the mitogen-activated protein kinase MAPK pathway in regulating ChAT expression in a murine septal cell line. Surprisingly we found that PD98059 and U0126 two structurally distinct inhibitors of MAPK kinase MEK1 increased both basal and CNTF-induced ACh production. Transient transfections with ChAT promoter-luciferase reporter construct demonstrated synergy between PD98059 and CNTF at the transcriptional level. Moreover in cotransfection studies overexpression of constitutively activated MEK1 completely abrogated the CNTF-mediated induction of the reporter. Blocking MEK1 did not signihcantly alter CNTF-induced Tyr705 phosphorylation of the principal mediator of the CNTF pathway the transcription factor Stat3. However PD98059 inhibited Ser727 phosphorylation of Stat3 demonstrating that the latter is MEK1-dependent. Taken together these results indicate that activation of the MEK1 MAPK pathway inhibits the CNTF-mediated stimulation of ChAT expression possibly as a part of a feedback mechanism. Keywords acetylcholine choline acetyltransferase MAP kinase ciliary neurotrophic factor Stat3. Biosynthesis of the neurotransmitter acetylcholine ACh from choline and acetyl coenzyme A is catalyzed by the enzyme choline acetyltransferase ChAT acetyl-CoA cho-line O-acetylotransferase EC 1 . Following synthesis ACh is transported into synaptic vesicles by vesicular acetylcholine .

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