title: IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based inhibition motif (ITIM) containing isoform.
abstract: BACKGROUND
  Interferon regulatory factor-1 (IRF-1) is a master regulator of IFN-γ induced gene transcription. Previously we have shown that IRF-1 transcriptionally induces CEACAM1 via an ISRE (Interferon-Stimulated Response Element) in its promoter. CEACAM1 pre-mRNA undergoes extensive alternative splicing (AS) generating isoforms to produce either a short (S) cytoplasmic domain expressed primarily in epithelial cells or as an ITIM-containing long (L) isoform in immune cells.
  
  
  METHODS
  The transcriptional and molecular mechanism of CEACAM1 minigenes AS containing promoter ISREs mutations in the breast epithelial, MDA-MB-468, cell line was detected using flow cytometry. In addition, transcriptome sequencing was utilized to determine whether IRF-1 could direct the AS of other genes as well. Tumor xenografts were used to evaluate CEACAM1 isoform expression on the leading edge of breast tumor cells.
  
  
  RESULTS
  In the present study, we provide evidence that CEACAM1's promoter and variable exon 7 cross-talk allowing IRF-1 to direct AS events. Transcriptome sequencing shows that IRF-1 can also induce the global AS of genes involved in regulation of growth and differentiation as well as genes of the cytokine family. Furthermore, MDA-MB-468 cells grown as tumor xenografts exhibit an AS switch to the L-isoform of CEACAM1, demonstrating that an in vivo inflammatory milieu is also capable of generating the AS switch, similar to that found in human breast cancers Mol Cancer 7:46, 2008.
  
  
  CONCLUSIONS
  The novel AS regulatory activities attributed to IRF-1 indicate that the IFN-γ response involves a global change in both gene transcription and AS in breast epithelial cells.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dery
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: David
authors.initials: D
authors.lastname: Grunert
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: Tung
authors.initials: T
authors.lastname: Ngyuen
authors.forename: Celeste
authors.initials: C
authors.lastname: Cheung
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
authors.affiliation: Departments of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA. jshively@coh.org.
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061626:Immunoreceptor Tyrosine-Based Inhibition Motif / Q000235:genetics*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D020033:Protein Isoforms / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D050856:Interferon Regulatory Factor-1; D020033:Protein Isoforms; D007371:Interferon-gamma