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Regulation of the plasminogen activator inhibitor type-2 gene in monocytes:
localization of an upstream transcriptional silencer
TM Antalis, E Costelloe, J Muddiman, S Ogbourne and K Donnan
Queensland Cancer Fund Experimental Oncology Unit, Queensland Institute of
Medical Research, Brisbane, Australia.
Transcriptional regulation of the plasminogen activator inhibitor type- 2
(PAI-2) gene appears to be an important factor in the response of
mononuclear phagocytes to inflammation. We have investigated here the
molecular basis for PAI-2 synthesis in monocytic cells by reporter gene
deletion analysis. A DNA fragment containing 5.1 kb of 5' flanking region
through to the start of the second exon was fused to a chloramphenicol
acetyl transferase (CAT) reporter gene, transfected into macrophage and
nonmacrophage cells and tested for PAI-2 promoter- directed CAT activity in
the presence and absence of phorbol ester. Deletion analysis showed the
existence of three major transcription regulatory regions. (1) A positive
regulatory region contained in the proximal promoter mediates basal
transcription and 12-phorbol 13- myristate acetate inducibility. (2) A
negative regulatory region, or silencer, present between -1977 and -1675,
was found to repress PAI-2 promoter activity in an orientation- and
position-independent manner, but not in a cell-specific manner. (3) A
second positive regulatory element, located upstream between approximately
-5100 and -3300, appears to overcome inhibition mediated by the silencer in
a cell- specific manner, suggesting a mechanism for the regulation of this
gene. We have localized the motif responsible for silencer activity to a
28-bp DNA sequence containing a unique 12-bp palindrome centered at an Xba
I restriction enzyme site, CTCTCTAGAGAG, which is designated the
PAI-2-upstream silencer element-1 (PAUSE-1). This element binds a specific
PAUSE-1 binding factor as determined by mobility shift analysis. We
conclude that PAI-2 gene transcription is regulated by both positive and
negative control mechanisms that may be important for the regulation of
other genes as well.
Volume 88,
Issue 10,
pp. 3686-3697,
11/15/1996
Copyright © 1996 by The American Society of Hematology
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