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, Stephane Perrier, Margaret M. Florence, Ana M. Schor, Seth L. Schor

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)10742-10750
    Number of pages9
    JournalCancer Research
    Volume65
    Issue number23
    DOIs
    Publication statusPublished - 2005

    Fingerprint

    RNA Precursors
    Cytokines
    Messenger RNA
    3' Untranslated Regions
    Fibroblasts
    Protein Isoforms
    Cell Nucleus Active Transport
    Transforming Growth Factors
    Reporter Genes
    Fibronectins
    Northern Blotting
    Introns
    Genes
    Neoplasms
    Proteins
    RNA

    Cite this

    @article{6eee2eca45b5477cb8123af9fedc3a61,
    title = "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",
    abstract = "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-{\ss}1 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.",
    author = "Kay, {Richard A.} and Ellis, {Ian R.} and Jones, {Sarah J.} and Stephane Perrier and Florence, {Margaret M.} and Schor, {Ana M.} and Schor, {Seth L.}",
    note = "dc.publisher: American Association for Cancer Research Reports that MSF expression is controlled by a novel process involving generation of a nuclear-sequestered pre-mRNA, followed by cleavage of its 3’-UTR to produce the mature message. These observations provide a critical insight into the manner by which MSF expression may be manipulated in a clinically efficacious manner.",
    year = "2005",
    doi = "10.1158/0008-5472.CAN-05-2038",
    language = "English",
    volume = "65",
    pages = "10742--10750",
    journal = "Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research",
    number = "23",

    }

    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. / Kay, Richard A.; Ellis, Ian R.; Jones, Sarah J.; Perrier, Stephane; Florence, Margaret M.; Schor, Ana M.; Schor, Seth L.

    In: Cancer Research, Vol. 65, No. 23, 2005, p. 10742-10750.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - 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

    AU - Kay, Richard A.

    AU - Ellis, Ian R.

    AU - Jones, Sarah J.

    AU - Perrier, Stephane

    AU - Florence, Margaret M.

    AU - Schor, Ana M.

    AU - Schor, Seth L.

    N1 - dc.publisher: American Association for Cancer Research Reports that MSF expression is controlled by a novel process involving generation of a nuclear-sequestered pre-mRNA, followed by cleavage of its 3’-UTR to produce the mature message. These observations provide a critical insight into the manner by which MSF expression may be manipulated in a clinically efficacious manner.

    PY - 2005

    Y1 - 2005

    N2 - 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.

    AB - 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.

    U2 - 10.1158/0008-5472.CAN-05-2038

    DO - 10.1158/0008-5472.CAN-05-2038

    M3 - Article

    VL - 65

    SP - 10742

    EP - 10750

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 23

    ER -