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Papers In Press, published online ahead of print November 22, 2005
J. Biol. Chem, 10.1074/jbc.M510935200
Submitted on October 6, 2005
Revised on November 17, 2005
Accepted on November 22, 2005

Astrocyte-specific expression of the alpha 1-antichymotrypsin and glial fibrillary acidic protein genes requires activator protein-1

Sunita M. Gopalan, Katarzyna M. Wilczynska, Barbara S. Konik, Lauren Bryan, and Tomasz Kordula

Biochemistry Dept., Virginia Commonwealth University, Richmond, VA 23298

Corresponding Author: tkordula{at}vcu.edu

An amyloid-associated serine proteinase inhibitor (serpin)1, 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 that 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 IL-1-treated cells. Moreover, functional c-jun is required for the expression of ACT in glioma cells since both transient or 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 was 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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