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Molecular and Cellular Biology, February 2001, p. 1228-1238, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1228-1238.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

hnRNP F Influences Binding of a 64-Kilodalton Subunit of Cleavage Stimulation Factor to mRNA Precursors in Mouse B Cells

Kristen L. Veraldi,1 George K. Arhin,2 Kathleen Martincic,1 Ling-Hsiu Chung-Ganster,1 Jeffrey Wilusz,2 and Christine Milcarek1,*

Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,1 and Department of Microbiology and Molecular Genetics, UMDNJ-NJ Medical School, Newark, New Jersey 071032

Received 31 May 2000/Returned for modification 7 July 2000/Accepted 16 November 2000

Previous studies on the regulation of polyadenylation of the immunoglobulin (Ig) heavy-chain pre-mRNA argued for trans-acting modifiers of the cleavage-polyadenylation reaction operating differentially during B-cell developmental stages. Using four complementary approaches, we demonstrate that a change in the level of hnRNP F is an important determinant in the regulated use of alternative polyadenylation sites between memory and plasma stage B cells. First, by Western analyses of cellular proteins, the ratio of hnRNP F to H or H' was found to be higher in memory B cells than in plasma cells. In memory B cells the activity of CstF-64 binding to pre-mRNA, but not its amount, was reduced. Second, examination of the complexes formed on input pre-mRNA in nuclear extracts revealed large assemblages containing hnRNP H, H', and F but deficient in CstF-64 in memory B-cell extracts but not in plasma cells. Formation of these large complexes is dependent on the region downstream of the AAUAAA in pre-mRNA, suggesting that CstF-64 and the hnRNPs compete for a similar region. Third, using a recombinant protein we showed that hnRNP F could bind to the region downstream of a poly(A) site, block CstF-64 association with RNA, and inhibit the cleavage reaction. Fourth, overexpression of recombinant hnRNP F in plasma cells resulted in a decrease in the endogenous Ig heavy-chain mRNA secretory form-to-membrane ratio. These results demonstrate that mammalian hnRNP F can act as a negative regulator in the pre-mRNA cleavage reaction and that increased expression of F in memory B cells contributes to the suppression of the Ig heavy-chain secretory poly(A) site.

* Corresponding author. Mailing address: Department of Molecular Genetics and Biochemistry and Graduate Program in Immunology, University of Pittsburgh School of Medicine, W1257 Biomedical Science Tower, Pittsburgh, PA 15261. Phone: (412) 648-9098. Fax: (412) 624-1401. E-mail: milcarek{at}pitt.edu.

Molecular and Cellular Biology, February 2001, p. 1228-1238, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1228-1238.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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