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Molecular and Cellular Biology, October 2002, p. 7242-7257, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7242-7257.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Calreticulin Interacts with C/EBP and C/EBPß mRNAs and Represses Translation of C/EBP Proteins

Department of Pathology and Huffington Center on Aging,² Departments of Medicine and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030¹

Received 25 March 2002/ Returned for modification 15 May 2002/ Accepted 8 July 2002

We previously identified an RNA binding protein, CUGBP1, which binds to GCN repeats located within the 5' region of C/EBPß mRNAs and regulates translation of C/EBPß isoforms. To further investigate the role of RNA binding proteins in the posttranscriptional control of C/EBP proteins, we purified additional RNA binding proteins that interact with GC-rich RNAs and that may regulate RNA processing. In HeLa cells, the majority of GC-rich RNA binding proteins are associated with endogenous RNA transcripts. The separation of these proteins from endogenous RNA identified several proteins in addition to CUGBP1 that specifically interact with the GC-rich 5' region of C/EBPß mRNA. One of these proteins was purified to homogeneity and was identified as calreticulin (CRT). CRT is a multifunctional protein involved in several biological processes, including interaction with and regulation of rubella virus RNA processing. Our data demonstrate that both CUGBP1 and CRT interact with GCU repeats within myotonin protein kinase and with GCN repeats within C/EBP and C/EBPß mRNAs. GCN repeats within these mRNAs form stable SL structures. The interaction of CRT with SL structures of C/EBPß and C/EBP mRNAs leads to inhibition of translation of C/EBP proteins in vitro and in vivo. Deletions or mutations abolishing the formation of SL structures within C/EBP and C/EBPß mRNAs lead to a failure of CRT to inhibit translation of C/EBP proteins. CRT-dependent inhibition of C/EBP is sufficient to block the growth-inhibitory activity of C/EBP. This finding further defines the molecular mechanism for posttranscriptional regulation of the C/EBP and C/EBPß proteins.

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