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Control of plasminogen-activator inhibitor type 2 gene expression in the differentiation of monocytic cells
journal contribution
posted on 2023-05-16, 16:50 authored by Antalis, TM, Joanne DickinsonJoanne DickinsonPlasminogenâ€activator inhibitor type 2 (PAIâ€2) is a potent and primary inhibitor of urokinaseâ€type plasminogen activator. Its production in monocytic cells is thought to play an important role in the control of localized proteolysis at sites of invasion as occurs in the control of inflammatory processes, tumor invasion and cellular differentiation. Therefore, we have investigated the mechanisms responsible for the regulation of PAIâ€2 gene expression in differentiating monocytic cells using the human promyelocytic cell line, HLâ€60, as a model. These cells are induced to differentiate to a macrophageâ€like phenotype in response to phorbol ester [4â€phorbolâ€12â€myristate 13â€acetate (PMA)]. The levels of PAIâ€2 mRNA are barely detectable in undifferentiated cells, however, activation with PMA is associated with a rapid induction of PAIâ€2 transcripts, reaching a maximum of 25â€fold in 4 h. Nuclear run on assays demonstrate that this induction is related primarily to an enhanced rate of gene transcription. Inhibition of de novo protein synthesis by cycloheximide increases PAIâ€2 mRNA levels in both resting (sevenfold) and PMAâ€treated cells (fivefold) after 4 h, but has no detectable effect on the rate of PAIâ€2 gene transcription. The initial apparent halfâ€life of the induced PAIâ€2 mRNA, determined by actinomycinâ€dâ€decay experiments, is very short, 32 min, suggesting rapid turnover. Furthermore, the PAIâ€2 mRNA transcript is stabilized in the presence of cycloheximide, with a fourfold increase in the observed halfâ€life. The results demonstrate that PAIâ€2 gene expression is regulated through postâ€transcriptional mechanisms in undifferentiated cells, while both transcriptional and postâ€transcriptional events govern the level of PAIâ€2 transcripts in cells differentiated along the monocytic pathway. Destabilization of the PAIâ€2 transcript may be associated with (A + U)â€rich sequences found in the 3′â€untranslated region of PAIâ€2 mRNA. The short half life and rapid, strong induction of PAIâ€2 point to an important, perhaps crucial, role in the differentiation of monocyte cells. Copyright © 1992, Wiley Blackwell. All rights reserved
History
Publication title
European Journal of BiochemistryVolume
205Pagination
203-209ISSN
0014-2956Department/School
Menzies Institute for Medical ResearchPublisher
Blackwell Publishing LtdPlace of publication
9600 Garsington Rd, Oxford, England, Oxon, Ox4 2DgRepository Status
- Restricted