1: J Biol Chem. 2003 May 2;278(18):15794-9. Epub 2003 Feb 24. 

Independent and cooperative activation of chromosomal c-fos promoter by STAT3.

Yang E, Lerner L, Besser D, Darnell JE Jr.

Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY
10021, USA.

The c-fos gene was one of the earliest vertebrate genes shown to be
transcriptionally induced by growth factors. Intensive study of the promoter of
c-fos (-325 to -80) by transient or permanent transfections of synthetic DNA
constructs has repeatedly shown the importance of several sequence elements and
the resident nuclear proteins that bind them (e.g. ternary complex factor/ELK1;
serum response factor, cAMP response element-binding protein/amino-terminal
fragment/AP-1). However these studies have left unanswered numerous questions
about the role of these proteins in the regulation of the native chromosomal
gene. In particular, the role of a site in this enhancer that binds STATs has
been controversial. We present evidence here that STAT3 and not STAT1
accumulates on the chromosomal c-fos promoter and provides a boost to
transcription without the activation of resident nuclear proteins through serine
kinases. Also, when resident nuclear proteins such as ELK1 are activated to
varying extents by mitogen-activated protein kinase pathways, STAT3 activation
provides a 2-fold boost regardless of the final level of activated
transcription. Thus the several proteins that interact with the c-fos enhancer
apparently can act either in a cooperative or independent manner to achieve very
different levels of transcription.

PMID: 12600988 [PubMed - indexed for MEDLINE]


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2: J Pharmacol Exp Ther. 2002 Aug;302(2):516-24. 

Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus:
pharmacological and signal transduction mechanisms.

Bachtell RK, Tsivkovskaia NO, Ryabinin AE.

Department of Behavioral Neuroscience, Oregon Health and Science University,
3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.

Mapping inducible transcription factors has shown that the Edinger-Westphal
nucleus is preferentially sensitive to alcohol intoxication. Herein, we
characterize the pharmacological and signal transduction mechanisms related to
alcohol-induced c-Fos expression in Edinger-Westphal neurons. Using
immunohistochemistry, we show that pretreatment with gamma-aminobutyric acid
(GABA)-ergic antagonists (4 mg/kg bicuculline and 45 mg/kg pentylenetetrazole)
attenuates induction of c-Fos expression by alcohol (2.4 g/kg, intraperitoneal).
In addition, 10 mg/kg
2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)4,5-dihydro-1H-imidazole (RX
821002), an alpha(2A/D)-adrenoceptor antagonist, and 20 mg/kg haloperidol, a
dopamine antagonist, also block alcohol-induced c-Fos expression in
Edinger-Westphal neurons. No effects were seen in alcohol-induced c-Fos after
the pretreatment of 20 mg/kg propranolol (beta-adrenoceptor antagonist), 10
mg/kg 2-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethy)-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC 239)
(alpha(2B/C)-adrenoceptor antagonist), or 30 mg/kg naltrexone (opioid
antagonist). Although positive modulators for the GABA(A) receptor (20 mg/kg
3alpha-hydroxy-5alpha-pregnan-20-one and 10-30 mg/kg chlordiazepoxide) and
opioid receptor (10 mg/kg morphine) produced significant elevations, agonists
for alpha(2)-adrenoceptors (clonidine) and dopamine receptors (apomorphine) had
no effect on Edinger-Westphal c-Fos expression. These findings suggest that
alcohol-induced c-Fos expression in Edinger-Westphal results from direct
interactions with GABA(A) receptors, which are modified by
alpha(2A/D)-adrenoceptors and dopamine receptors. Also using
immunohistochemistry to identify potential intracellular mechanisms associated
with alcohol-induced c-Fos expression in Edinger-Westphal, we show
time-dependent increases in serine 727 phospho-signal transducer and activator
of transcription 3 (Stat3) but no changes in phospho-cAMP response
element-binding protein and phospho-Elk1. Time-dependent increases in
phospho-extracellular signal-regulated kinase (ERK) 1/2 were found to occur
simultaneously with increases in serine 727 phospho-Stat3. Finally, blockade of
ERK 1/2 phosphorylation with the mitogen-activated protein kinase (MEK) 1/2
inhibitor SL327 blocked alcohol-induced c-Fos expression, suggesting that
alcohol induces c-Fos in Edinger-Westphal neurons through activation of the
MEK1/2-ERK1/2-Stat3 pathway.

PMID: 12130710 [PubMed - indexed for MEDLINE]


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