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Mol Cancer. 2008 May 28;7:46. doi: 10.1186/1476-4598-7-46.

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

Author information

1
Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. sgaur@coh.org

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.

PMID:
18507857
PMCID:
PMC2490704
DOI:
10.1186/1476-4598-7-46
[Indexed for MEDLINE]
Free PMC Article

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