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

Richard A. Kay, Ian R. Ellis, Sarah J. Jones, Stéphane Perrier, Margaret M. Florence, Ana M. Schor, Seth L. Schor
2005 Cancer Research  
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 3V 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
more » ... 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 3V -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-B1 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 3V -UTR retained coding sequence within the nucleus. We conclude that expression of MSF protein is regulated by 3V -UTR truncation of the 5.9-kb nuclear-sequestered "precursor" MSF mRNA and nuclear export of mature 2.1-kb message. Inducible 3V -UTR processing represents a novel regulatory mechanism involved in cancer pathogenesis that may open new avenues for therapeutic gene delivery. (Cancer Res 2005; 65(23): 10742-9) Requests for reprints:
doi:10.1158/0008-5472.can-05-2038 pmid:16322219 fatcat:xbxzpz7s6nbovnvtdwfv4bdbuu