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Molecular and Cellular Biology, December 1998, p. 7371-7382, Vol. 18, No. 12
Department of Molecular
Pharmacology1 and
Mayer Cancer Biology
Research Laboratory, Department of Radiation
Oncology,3 Stanford University School of
Medicine, Stanford, California 94305-5332, and
Laboratoire
de Biométrie, Génétique et Biologie des Populations,
UMR CNRS 5558, Université Claude Bernard
Received 8 June 1998/Returned for modification 10 August
1998/Accepted 19 August 1998
The putative function of highly conserved regions (HCRs) within 3'
untranslated regions (3'UTRs) as regulatory RNA sequences was
efficiently and quantitatively assessed by using modular retroviral vectors. This strategy led to the identification of HCRs that alter
gene expression in response to oxidative or mitogenic stress. Databases
were screened for UTR sequences of >100 nucleotides that had retained
70% identity over more than 300 million years of evolution. The
effects of 10 such HCRs on a standard reporter mRNA or protein were
studied. To this end, we developed a modular retroviral vector that can
allow for a direct comparison of the effects of different HCRs on gene
expression independent of their gene-intrinsic 5'UTR, promoter, protein
coding region, or poly(A) sequence. Five of the HCRs tested decreased
mRNA steady-state levels 2- to 10-fold relative to controls, presumably
by altering mRNA stability. One HCR increased translation, and one
decreased translation. Elevated mitogen levels caused four HCRs to
increase protein levels twofold. One HCR increased protein levels
fourfold in response to hypoxia. Although nonconserved UTR sequences
may also have a role, these results provide evidence that sequences that are highly conserved during evolution are good candidates for RNA
motifs with posttranscriptional regulatory functions in gene expression.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Highly Conserved RNA Sequences That Are Sensors of
Environmental Stress

Lyon 1, 69622 Villeurbanne Cedex, France2
*
Corresponding author. Mailing address: Department of
Molecular Pharmacology, 300 Pasteur Dr., Stanford University School of Medicine, Stanford, CA 94305-5332. Phone: (650) 723-6209. Fax: (650)
725-2952. E-mail: hblau{at}cmgm.stanford.edu.
Present address: Ontogeny, Inc., Cambridge, MA 02138-1118.
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