Altered splicing of CEACAM1 in breast cancer: identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms.
Altered splicing of CEACAM1 in breast cancer: identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms.
复制标题
DOI：
10.1186/1476-4598-7-46
复制
发表时间：
2008-05-28
期刊：
影响因子：
37.3
通讯作者：
Gaur RK
中科院分区：
文献类型：
--
作者：
Gaur S;Shively JE;Yen Y;Gaur RK
癌胚抗原相关细胞黏附分子1(CEACAM1)是一种在多种细胞类型中表达的细胞黏附分子，是一种可能的肿瘤抑制基因。CEACAM1的选择性剪接产生11种不同的剪接变体，其中包括1-4个胞外结构域，胞外结构域由外显子7的排除(CEACAM1-S)或包含(CEACAM1-L)产生。在啮齿类动物的研究表明，抑制结肠肿瘤细胞生长需要最佳比例的CEACAM1剪接变体。我们发现CEACAM1以组织特异性的方式表达，其短(CEACAM1-S)和长(CEACAM1-L)细胞质结构域剪接变异体的比例有显著差异。重要的是，我们发现在正常乳腺组织和乳腺癌标本中S：L亚型的比例存在显著差异，这表明CEACAM1剪接改变在肿瘤发生中可能发挥重要作用。此外，我们还发现了CEACAM1选择性剪接所需的两个调控顺式作用元件。这些调控元件被人的β-珠蛋白外显子序列取代，导致作为主要产物的外显子7跳过。有趣的是，当外显子7插入β-珠蛋白报告基因导致其跳过时，外显子7与侧翼内含子序列一起重现了CEACAM1的选择性剪接。我们的结果表明，调控元件网络控制着CEACAM1的选择性剪接。这些发现可能对CEACAM1相关人类疾病的治疗方式具有重要意义。
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. 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 β-globin exon sequences resulted in exon 7-skipped mRNA as the predominant product. Interestingly, while insertion of exon 7 in a β-globin reporter gene resulted in its skipping, exon 7 along with the flanking intron sequences recapitulated the alternative splicing of CEACAM1. 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.
登录
查看更多内容
影响因子：
56.9
作者：
Cheng, J;Kapranov, P;Gingeras, TR
通讯作者：
Gingeras, TR
影响因子：
4.5
作者：
Kim, DS;Gusti, V;Gaur, RK
通讯作者：
Gaur, RK
DOI：
10.1084/jem.20030437
发表时间：
2004-02-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iijima H;Neurath MF;Nagaishi T;Glickman JN;Nieuwenhuis EE;Nakajima A;Chen D;Fuss IJ;Utku N;Lewicki DN;Becker C;Gallagher TM;Holmes KV;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
4.4
作者：
Chen, DH;Iijima, H;Blumberg, RS
通讯作者：
Blumberg, RS
影响因子：
4.8
作者：
Kirshner, J;Schumann, D;Shively, JE
通讯作者：
Shively, JE