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Granulocyte-macrophage colony-stimulating factor mRNA stabilization
enhances transgenic expression in normal cells and tissues
LE Rajagopalan, JK Burkholder, J Turner, J Culp, NS Yang and JS Malter
Department of Pathology and Laboratory Medicine, University of Wisconsin
Medical School, Madison 53792-2472, USA.
To increase transgenic production of granulocyte-macrophage colony-
stimulating factor (GM-CSF), we mutated the mRNA's 3'-untranslated region,
AUUUA instability elements. Expression vectors containing human or murine
GM-CSF cDNAs coding for wild-type (GM-AUUUA) or mutant versions with
reiterated AUGUA repeats (GM-AUGUA) were transfected into cells in culture
or animals using particle-mediated gene-transfer technology. Normal
peripheral blood mononuclear cells accumulated 20- fold greater levels of
GM-CSF mRNA and secreted comparably greater amounts of cytokine after
transfection with hGM-AUGUA expression vectors versus hGM-AUUUA. hGM-AUGUA
mRNA was fivefold more stable (t 1/2 = 95 minutes) than hGM-AUUUA mRNA (t
1/2 = 20 minutes), accounting for elevated steady-state levels.
Transfection site extracts and serum samples obtained 24 hours after gene
transfer of hGM-AUGUA cDNA into mouse skin contained greater than 32 ng/mL
and 650 pg/mL of GM-CSF protein, respectively, compared with 0.33 ng/mL and
less than 8 pg/mL for hGM-AUUUA cDNA. GM-CSF produced from mGM-AUGUA cDNA
transfected into rat abdominal epidermis induced a profound neutrophil
infiltrate. These data suggest a novel strategy for enhanced production of
biologically active cytokines by normal cells after in vivo gene transfer.
Volume 86,
Issue 7,
pp. 2551-2558,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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