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Molecular and Cellular Biology, October 1999, p. 6898-6905, Vol. 19, No. 10
Department of Cell Biology, The Lerner
Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195
Received 5 May 1999/Accepted 9 July 1999
Ceruloplasmin (Cp) is an acute-phase protein with ferroxidase,
amine oxidase, and pro- and antioxidant activities. The primary site of
Cp synthesis in human adults is the liver, but it is also synthesized
by cells of monocytic origin. We have shown that gamma interferon
(IFN-
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Delayed Translational Silencing of Ceruloplasmin
Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role
of the 3' Untranslated Region
) induces the synthesis of Cp mRNA and protein in monocytic
cells. We now report that the induced synthesis of Cp is terminated by
a mechanism involving transcript-specific translational repression. Cp
protein synthesis in U937 cells ceased after 16 h even in the
presence of abundant Cp mRNA. RNA isolated from cells treated with
IFN- for 24 h exhibited a high in vitro translation rate,
suggesting that the transcript was not defective. Ribosomal association
of Cp mRNA was examined by sucrose centrifugation. When Cp synthesis
was high, i.e., after 8 h of IFN- treatment, Cp mRNA was
primarily associated with polyribosomes. However, after 24 h, when
Cp synthesis was low, Cp mRNA was primarily in the nonpolyribosomal
fraction. Cytosolic extracts from cells treated with IFN- for
24 h, but not for 8 h, contained a factor which blocked in
vitro Cp translation. Inhibitor expression was cell type specific and
present in extracts of human cells of myeloid origin, but not in
several nonmyeloid cells. The inhibitory factor bound to the 3'
untranslated region (3'-UTR) of Cp mRNA, as shown by restoration of in
vitro translation by synthetic 3'-UTR added as a "decoy" and
detection of a binding complex by RNA gel shift analysis. Deletion
mapping of the Cp 3'-UTR indicated an internal 100-nucleotide region of
the Cp 3'-UTR that was required for complex formation as well as for
silencing of translation. Although transcript-specific translational
control is common during development and differentiation and global
translational control occurs during responses to cytokines and stress,
to our knowledge, this is the first report of translational silencing
of a specific transcript following cytokine activation.
*
Corresponding author. Mailing address: Department of
Cell Biology, The Lerner Research Institute/NC10, Cleveland Clinic
Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216)
444-8053. Fax: (216) 444-9404. E-mail: foxp{at}ccf.org.
Molecular and Cellular Biology, October 1999, p. 6898-6905, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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