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J. Biol. Chem., Vol. 278, Issue 4, 2317-2326, January 24, 2003
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From the Laboratorio de Biología Molecular, Departamento de
Química Biológica, Facultad de Ciencias Exactas y
Naturales, Universidad de Buenos Aires, Pabellón II Piso 4, Ciudad Universitaria, 1428 Buenos Aires, Argentina
Activation protein-1
(AP-1) transcription factors are early response genes involved in a
diverse set of transcriptional regulatory processes. The phorbol ester
12-O-tetradecanoylphorbol-13-acetate (TPA) is often used to
induce AP-1 activity. The purpose of this work was to explore the
molecular mechanisms involved in the TPA regulation of ubiquitous
5-aminolevulinate synthase (ALAS) gene expression, the first and
rate-controlling step of the heme biosynthesis. Previous analysis of
the 5'-flanking sequence of ALAS revealed the existence of two
cAMP-response elements (CRE) required for basal and cAMP-stimulated
expression. The fragment
Inhibitory Effect of AP-1 Complex on 5-Aminolevulinate Synthase
Gene Expression through Sequestration of cAMP-response Element Protein
(CRE)-binding Protein (CBP) Coactivator*
,
833 to +42 in the 5'-flanking region of rat
ALAS gene was subcloned into a chloramphenicol acetyltransferase (CAT)
reporter vector. The expression vector pALAS/CAT produced a significant
CAT activity in transiently transfected HepG2 human hepatoma cells,
which was repressed by TPA. Sequence and deletion analysis detected a
TPA response element (TRE), located between 261 and 255 (TRE-ALAS), that was critical for TPA regulation. We demonstrated that c-Fos, c-Jun, and JunD are involved in TPA inhibitory effect due to their ability to bind TRE-ALAS, evidenced by supershift analysis and their
capacity to repress promoter activity in transfection assays. Repression of ALAS promoter activity by TPA treatment or Fos/Jun overexpression was largely relieved when CRE protein-binding protein or
p300 was ectopically expressed. When the TRE site was placed in a
different context with respect to CRE sites, it appeared to act as a
transcriptional enhancer. We propose that the decrease in ALAS basal
activity observed in the presence of TPA may reflect a lower ability of
this promoter to assemble the productive pre-initiation complex due to
CRE protein-binding protein sequestration. We also suggest that the
transcriptional properties of this AP-1 site would depend on a
spatial-disposition-dependent manner with respect to the
CRE sites and to the transcription initiation site.
*
This work was supported by research grants from the
Universidad de Buenos Aires and Consejo Nacional de Investigaciones
Científicas y Técnicas.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
A Research Fellow of the Consejo Nacional de Investigaciones
Científicas y Técnicas.
§
To whom correspondence should be addressed. Tel.: 54-11-4821-4893;
Fax: 54-11-4576-3342; E-mail: ecanepa@qb.fcen.uba.ar.
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