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)10742-10749
Number of pages8
JournalCancer Research
Volume65
Issue number23
DOIs
Publication statusPublished - Dec 2005

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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",
month = "12",
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language = "English",
volume = "65",
pages = "10742--10749",
journal = "Cancer Research",
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publisher = "American Association for Cancer Research",
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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. / 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, 12.2005, p. 10742-10749.

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 - 2005/12

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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

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SP - 10742

EP - 10749

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

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