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PMID:9712850

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Citation

Lee, NH and Malek, RL (1998) Nerve growth factor regulation of m4 muscarinic receptor mRNA stability but not gene transcription requires mitogen-activated protein kinase activity. J. Biol. Chem. 273:22317-25

Abstract

Nerve growth factor (NGF) up-regulated steady-state levels of m4 muscarinic acetylcholine receptor (mAChR) mRNA in PC12 cells. Up-regulation of mRNA levels was associated with a corresponding increase in mAChR binding sites. Two other growth factors, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), up-regulated m4 mRNA and mAChR binding sites. Treatment of PC12 cells with NGF and bFGF, but not EGF, has previously been demonstrated to result in sustained activation of mitogen-activated protein kinase (MAPK). Analogously, NGF and bFGF, but not EGF, increased the stability of m4 mRNA in PC12 cells. In HER-PC12 cells, a clonal PC12 cell transfectant overexpressing EGF receptors and displaying sustained MAPK activation upon receptor stimulation, EGF treatment stabilized the m4 transcript. A synthetic inhibitor of MAPK kinase, PD98059, inhibited growth factor-induced stabilization of the m4 transcript in both PC12 and HER-PC12 cells. These findings demonstrate that the MAPK pathway is involved in transcript stabilization. Cycloheximide pretreatment abolished the post-transcriptional effect of NGF, indicating that de novo protein synthesis was required for the observed increase in m4 mRNA stability. By contrast, cycloheximide had no discernible post-transcriptional effect if added after NGF treatment, suggesting that an inducible yet stable protein factor was involved in m4 mRNA decay. An unusually well conserved 137 nucleotides of m4 3'-untranslated region has been identified by sequence comparison with other mRNAs that are post-transcriptionally regulated by NGF. In PC12 cells that heterologously overexpress this region, we demonstrate that NGF no longer stabilizes endogenous m4 mRNA. This conserved region probably represents an NGF-responsive element involved in mRNA stability regulation. Finally, transcription of the m4 gene can be induced by all three growth factors but is not dependent on MAPK activity, unlike growth factor-induced m4 mRNA stabilization.

Links

PubMed

Keywords

Animals; Base Sequence; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Epidermal Growth Factor/pharmacology; Fibroblast Growth Factor 2/pharmacology; Gene Expression Regulation/drug effects; Molecular Sequence Data; Nerve Growth Factors/pharmacology; PC12 Cells; RNA, Messenger/genetics; Rats; Receptor, Muscarinic M4; Receptors, Muscarinic/genetics; Sequence Homology, Nucleic Acid; Transcription, Genetic/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGF

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FGF2

involved_in

GO:0000187: activation of MAPK activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGF2

involved_in

GO:0007165: signal transduction

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGF

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000304: author statement supported by traceable reference used in manual assertion


F

Seeded From UniProt

complete

HUMAN:EGF

involved_in

GO:0045741: positive regulation of epidermal growth factor-activated receptor activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGF

enables

GO:0030297: transmembrane receptor protein tyrosine kinase activator activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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