期刊
JOURNAL OF NEUROCHEMISTRY
卷 98, 期 4, 页码 1302-1315出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2006.03976.x
关键词
glycoprotein 130; leukemia inhibitory factor; muscarinic; promoter; signal transducers and activators of transcription
资金
- NIGMS NIH HHS [GM07727, GM07108] Funding Source: Medline
- NINDS NIH HHS [NS30410, NS26920] Funding Source: Medline
Treatment of neuronal cells with leukemia inhibitory factor (LIF) results in increased M-2 muscarinic acetylcholine receptor promoter activity. We demonstrate here that multiple promoter elements mediate LIF stimulation of M-2 gene transcription. We identify a LIF inducible element (LIE) in the M-2 promoter with high homology to a cytokine-inducible ACTG-containing sequence in the vasoactive intestinal peptide promoter. Mutagenesis of both a STAT (signal transducers and activators of transcription) element and the LIE in the M-2 promoter is required to attenuate stimulation of M-2 promoter activity by LIF completely. Mobility shift assays indicate that a LIF-stimulated complex binds to a 70 base pair M-2 promoter fragment. Furthermore, a STAT element within this fragment can bind to LIF-stimulated nuclear STAT1 homodimers in vitro. Mutagenesis experiments show that cytokine-stimulated activation of M-2 promoter activity requires tyrosine residues on glycoprotein 130 (gp130) that are also required for both STAT1 and STAT3 activation. Dominant negative STAT1 or STAT3 can block LIF-stimulated M-2 promoter activity. Real-time RT-PCR analysis indicates that LIF-stimulated induction of M-2 mRNA is partially dependent on protein synthesis. These results show that regulation of M-2 gene transcription in neuronal cells by LIF occurs through a complex novel mechanism that is dependent on LIE, STAT and de novo protein synthesis.
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