Nucleic Acids Research, Vol 26, Issue 2 558-565, Copyright © 1998 by Oxford University Press
N Xu, P Loflin, CY Chen and AB Shyu
The widespread occurrence of AU-rich elements (AREs) in mRNAs encoding
proteins with diversified functions and synthesized under a vast variety of
physiological conditions suggests that AREs are involved in finely tuned
and stringent control of gene expression. Thus it is important to
investigate the regulation of ARE-mediated mRNA decay in a variety of
mammalian cells in different physiological states. The tetracycline
(Tet)-regulatory promoter system appears appropriate for these
investigations. However, we found that efficient degradation of mRNAs
bearing different AREs cannot be observed simply by blocking constitutive
transcription from the Tet-regulated promoter with Tet, possibly due to
saturation of the cellular decay machinery. In addition, deadenylation
kinetics and their relationship to mRNA decay cannot be adequately measured
under these conditions. To overcome these obstacles we have developed a new
strategy that employs the Tet- regulated promoter system to achieve a
transient burst of transcription that results in synthesis of a population
of cytoplasmic mRNAs fairly homogeneous in size. Using this new system we
show that ARE- destabilizing function, necessary for down-regulating mRNAs
for cytokines, growth factors and transcription factors, is maintained in
quiescent or growth-arrested cells as well as in saturation density-
arrested NIH 3T3 cells. We also demonstrate that the ARE-mediated decay
pathway is conserved between NIH 3T3 fibroblasts and K562 erythroblasts.
These in vivo observations support a broader role for AREs in the control
of cell growth and differentiation. In addition, we observed that there is
a significant difference in deadenylation and decay rates for beta-globin
mRNA expressed in these two cell lines. Deadenylation and decay of
beta-globin mRNA in K562 cells is extraordinarily slow compared with NIH
3T3 cells, suggesting that the increased stability gained by beta-globin
mRNA in K562 cells is mainly controlled at the deadenylation step. Our
strategy for studying mammalian mRNA turnover now permits a more general
application to different cell lines harboring the Tet-regulated system
under various physiological conditions.
ARTICLES
A broader role for AU-rich element-mediated mRNA turnover revealed by a new transcriptional pulse strategy
Department of Biochemistry and Molecular Biology, The University of Texas Houston Health Science Center, Medical School, Houston, TX 77030, USA.
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