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The Expression of Migration Stimulating Factor, a Potent Oncofetal Cytokine, Is Uniquely Controlled by 3'-Untranslated Region–Dependent Nuclear Sequestration of Its Precursor Messenger RNA

Unit of Cell and Molecular Biology, Dental School, University of Dundee, Dundee, United Kingdom

Requests for reprints: Seth L. Schor, Unit of Cell and Molecular Biology, Dental School, University of Dundee, Dundee DD1 4HR, United Kingdom. Phone: 44-1382-635991; Fax: 44-1382-635998; E-mail: S.L.Schor{at}dundee.ac.uk.

Migration stimulating factor (MSF) is a truncated oncofetal fibronectin isoform expressed by fetal and tumor-associated cells. MSF mRNA is distinguished from other fibronectin isoforms by its size (2.1 kb) and the inclusion of a specific intronic sequence at its 3' end. Initial Northern blot analysis with a MSF-specific probe indicated the presence of this 2.1-kb transcript and an additional unexpected 5.9-kb RNA present in both MSF-secreting (fetal) and nonsecreting (adult) fibroblasts. Our investigations into the nature of these transcripts and their relationship to MSF protein secretion revealed that the 5.9-kb mRNA is a second MSF-encoding transcript. Both these mRNAs have identical coding sequence and differ only in the length of their intron-derived 3'-untranslated region (UTR). The 5.9-kb MSF mRNA is retained in the nucleus whereas the 2.1-kb mRNA is not. MSF-secreting fetal fibroblasts have significantly lower nuclear levels of the 5.9-kb mRNA and correspondingly higher cytoplasmic levels of the 2.1-kb transcript than their nonsecreting adult counterparts. Adult fibroblasts induced to secrete MSF by treatment with transforming growth factor-ß1 displayed similar changes in their respective levels of MSF mRNA, but not those of a control gene. When cloned downstream of a reporter gene, only the longer 3'-UTR retained coding sequence within the nucleus. We conclude that expression of MSF protein is regulated by 3'-UTR truncation of the 5.9-kb nuclear-sequestered "precursor" MSF mRNA and nuclear export of mature 2.1-kb message. Inducible 3'-UTR processing represents a novel regulatory mechanism involved in cancer pathogenesis that may open new avenues for therapeutic gene delivery.

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