Altered splicing of CEACAM1 in breast cancer: identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms.

Abstract

BACKGROUND:

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cell adhesion molecule expressed in a variety of cell types is a putative tumor suppressor gene. Alternative splicing of CEACAM1 generates 11 different splice variants, which include 1-4 ectodomains with either short or long cytoplasmic domain generated by the exclusion (CEACAM1-S) or inclusion (CEACAM1-L) of exon 7. Studies in rodents indicate that optimal ratios of CEACAM1 splice variants are required to inhibit colonic tumor cell growth.

RESULTS:

We show that CEACAM1 is expressed in a tissue specific manner with significant differences in the ratios of its short (CEACAM1-S) and long (CEACAM1-L) cytoplasmic domain splice variants. Importantly, we find dramatic differences between the ratios of S:L isoforms in normal breast tissues versus breast cancer specimens, suggesting that altered splicing of CEACAM1 may play an important role in tumorogenesis. Furthermore, we have identified two regulatory cis-acting elements required for the alternative splicing of CEACAM1. Replacement of these regulatory elements by human beta-globin exon sequences resulted in exon 7-skipped mRNA as the predominant product. Interestingly, while insertion of exon 7 in a beta-globin reporter gene resulted in its skipping, exon 7 along with the flanking intron sequences recapitulated the alternative splicing of CEACAM1.

CONCLUSION:

Our results indicate that a network of regulatory elements control the alternative splicing of CEACAM1. These findings may have important implications in therapeutic modalities of CEACAM1 linked human diseases.

• Authors: Shikha Gaur, John E Shively, Yun Yen, Rajesh K Gaur
• Journal: Molecular cancer (Mol Cancer) Vol. 7 Pg. 46 (May 28 2008) ISSN: 1476-4598 [Electronic] England
• PMID: 18507857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, CD
• CD66 antigens
• Cell Adhesion Molecules
• Protein Isoforms

Topics

• Alternative Splicing (genetics)
• Antigens, CD (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Line, Tumor
• Cytoplasm (metabolism)
• Exons (genetics)
• Gene Expression Regulation, Neoplastic
• Health
• Humans
• Introns (genetics)
• Protein Isoforms (genetics, metabolism)
• Regulatory Sequences, Nucleic Acid