Ethanol inhibits brain-derived neurotrophic factor-mediated intracellular signaling and activator protein-1 activation in cerebellar granule neurons

被引:48
作者
Li, Z
Ding, M
Thiele, CJ
Luo, J [1 ]
机构
[1] W Virginia Univ, Sch Med, Robert C Brd Hlth Sci Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA
[2] Natl Inst Occupat Safety & Hlth, Pathol & Physiol Res Branch, Morgantown, WV 26506 USA
[3] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA
[4] Chinese Acad Sci, SIBS, Inst Nutr Sci, Shanghai, Peoples R China
关键词
apoptosis; development; fetal alcohol syndrome; neurotrophins; signal transduction; transcription factor;
D O I
10.1016/j.neuroscience.2004.03.028
中图分类号
Q189 [神经科学];
学科分类号
071006 [神经生物学];
摘要
Developmental exposure to ethanol causes profound damage to the cerebellum, ranging from aberration in neuronal differentiation to cell loss. As a major neurotrophic factor, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are expressed in the developing, as well as adult, cerebellum. Many neurotrophic effects of BDNF are mediated by gene transcription. We hypothesized that ethanol interfered with BDNF signaling and disrupted BDNF-regulated transcriptional activity. Using a transgenic mouse model expressing an activator protein-1 (AP-1) luciferase reporter construct, we demonstrated that BDNF stimulated AP-1 transactivation in cultured cerebellar granule neurons. This observation was validated by the study using a human neuronal cell line expressing inducible TrkB (TB8 neuroblastoma cells). BDNF induced AP-1 transactivation, as well as increased the binding activity of AP-1 protein complex to a DNA sequence containing AP-1 sites in TB8 cells. BDNF-mediated AP-1 activation was mediated by PI3K/Akt and JNK pathways; BDNF activated Akt and JNKs, and blocking these pathways significantly inhibited BDNF-stimulated AP-1 transactivation. More importantly, ethanol inhibited BDNF-mediated activation of PI3K/Akt and JNKs, and blocked BDNF-stimulated AP-1 activation. Since ethanol did not affect either the expression or autophosphorylation of TrkB, it could be concluded that the site of ethanol action was downstream of TrkB. The present study establishes that this AP-1 reporter transgenic mouse model is valuable for assessing AP-1 activity in the CNS neurons. Our results provide an insight into molecular mechanism(s) of ethanol action. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:149 / 162
页数:14
相关论文
共 98 条
[1]
In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-κB transcriptional activation in a rat fetal alcohol syndrome model [J].
Acquaah-Mensah, GK ;
Kehrer, JP ;
Leslie, SW .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 301 (01) :277-283
[2]
TRANSFORMING P21(RAS) MUTANTS AND C-ETS-2 ACTIVATE THE CYCLIN D1 PROMOTER THROUGH DISTINGUISHABLE REGIONS [J].
ALBANESE, C ;
JOHNSON, J ;
WATANABE, G ;
EKLUND, N ;
VU, D ;
ARNOLD, A ;
PESTELL, RG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (40) :23589-23597
[3]
THE ROLE OF JUN, FOS AND THE AP-1 COMPLEX IN CELL-PROLIFERATION AND TRANSFORMATION [J].
ANGEL, P ;
KARIN, M .
BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1072 (2-3) :129-157
[4]
The TrkB-Shc site signals neuronal survival and local axon growth via MEK and PI3-kinase [J].
Atwal, JK ;
Massie, B ;
Miller, FD ;
Kaplan, DR .
NEURON, 2000, 27 (02) :265-277
[5]
Baek JK, 1996, MOL BRAIN RES, V40, P161
[6]
Ethanol inhibits L1-mediated neurite outgrowth in postnatal rat cerebellar granule cells [J].
Bearer, CF ;
Swick, AR ;
O'Riordan, MA ;
Cheng, GH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (19) :13264-13270
[7]
Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation [J].
Behrens, A ;
Jochum, W ;
Sibilia, M ;
Wagner, EF .
ONCOGENE, 2000, 19 (22) :2657-2663
[8]
Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: Signal transduction cascades and site of ethanol action [J].
Bhave, SV ;
Ghoda, L ;
Hoffman, PL .
JOURNAL OF NEUROSCIENCE, 1999, 19 (09) :3277-3286
[9]
Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms [J].
Bonni, A ;
Brunet, A ;
West, AE ;
Datta, SR ;
Takasu, MA ;
Greenberg, ME .
SCIENCE, 1999, 286 (5443) :1358-1362
[10]
ALCOHOL-INDUCED NEURONAL LOSS IN DEVELOPING RATS - INCREASED BRAIN-DAMAGE WITH BINGE EXPOSURE [J].
BONTHIUS, DJ ;
WEST, JR .
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 1990, 14 (01) :107-118