Astrocyte-specific expression of the alpha1-antichymotrypsin and glial fibrillary acidic protein genes requires activator protein-1.
J Biol Chem
; 281(4): 1956-63, 2006 Jan 27.
Article
em En
| MEDLINE
| ID: mdl-16303762
ABSTRACT
An amyloid-associated serine proteinase inhibitor (serpin), alpha(1)-antichymotrypsin (ACT), is encoded by a gene located within the distal serpin subcluster on human chromosome 14q32.1. The expression of these distal serpin genes is determined by tissue-specific chromatin structures that allow their ubiquitous expression in hepatocytes; however, their expression is limited to a single ACT gene in astrocytes. In astrocytes and glioma cells, six specific DNase I-hypersensitive sites (DHSs) were found located exclusively in the 5'-flanking region of the ACT gene. We identified two enhancers that mapped to the two DHSs at -13 kb and -11.5 kb which contain activator protein-1 (AP-1) binding sites, both of which are critical for basal astrocyte-specific expression of ACT reporters. In vivo, these elements are occupied by c-jun homodimers in unstimulated cells and c-jun/c-fos heterodimers in interleukin-1-treated cells. Moreover, functional c-jun is required for the expression of ACT in glioma cells because both transient and stable inducible overexpression of dominant-negative c-jun(TAM67) specifically abrogates basal and reduces cytokine-induced expression of ACT. Expression-associated methylation of lysine 4 of histone H3 was also lost in these cells, but the DHS distribution pattern and global histone acetylation were not changed upstream of the ACT locus. Interestingly, functional AP-1 is also indispensable for the expression of glial fibrillary acidic protein (GFAP), which is an astrocyte-specific marker. We propose that AP-1 is a key transcription factor that, in part, controls astrocyte-specific expression of genes including the ACT and GFAP genes.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Alfa 1-Antiquimotripsina
/
Astrócitos
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Fator de Transcrição AP-1
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Proteína Glial Fibrilar Ácida
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos