Journal Article

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

Kujawski, Maciej, Yim, John H, Grunert, David, Cheung, Celeste, Ngyuen, Tung, Wu, Xiwei, Dery, Kenneth J, Shively, John E

2014

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V
• Subject: Alternative Splicing - genetics / Animals / Antigens, CD - biosynthesis / Antigens, CD - genetics / Autoimmune diseases / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Breast - metabolism / Breast - pathology / Breast cancer / Cancer Research / Cell adhesion & migration / Cell Adhesion Molecules - biosynthesis / Cell Adhesion Molecules - genetics / Cell Line, Tumor / Epithelial Cells - metabolism / Experiments / Female / Gene Expression Regulation, Neoplastic / Genes / Humans / Immune system / Immunoreceptor Tyrosine-Based Inhibition Motif - genetics / Interferon Regulatory Factor-1 - genetics / Interferon Regulatory Factor-1 - metabolism / Interferon-gamma - metabolism / Mice / Oncology / Protein Isoforms - biosynthesis / Rodents / Signal transduction / Studies / Xenograft Model Antitumor Assays