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


CONCLUSIONS
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.
Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. sgaur@coh.org
Shikha
S
Gaur
John E
JE
Shively
Yun
Y
Yen
Rajesh K
RK
Gaur
D017398:Alternative Splicing / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006262:Health; D006801:Humans; D007438:Introns / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D020033:Protein Isoforms