The fibronectin gene as a model for splicing and transcription studies

Abstract

The fibronectin (FN) gene has become paradigmatic to illustrate genome evolution by exon shuffling, generation of protein diversity by alternative mRNA splicing, and topological coordination between transcription and splicing. Alternative splicing in three sites of the primary transcript gives rise to multiple FN polypeptides. This process is cell type-, development- and age-regulated. The different FN variants seem to play specific roles in FN dimer secretion, blood clotting, adhesion to lymphoid cells, skin wound healing, atherosclerosis, and liver fibrosis. This review focuses on function assignment to the alternatively spliced segments, as well as on the external signals and cis-acting sequences that control the mechanisms of alternative splicing. We also discuss FN transcriptional regulation in response to viral transformation, growth factors, and cyclic AMP in the light of promoter architecture and its interaction with specific transcription factors. The relevance of FN RNA "tracks" as assembly lines of coordinated transcription and RNA processing is also addressed.

TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer

“…However, the breakpoints of deletions in aberrant TSG101 transcripts were not located at intron/ exon boundaries of the gene. While intra-exon splicing has been documented in some natural systems (Kornblihtt et al, 1996;West et al, 1996), this form of alternative splicing has been much less commonly described than inter-exon splicing, or`exon shu ing'. Recent reports consistent with ours also suggest that abnormal TSG101 transcripts may be a phenomenon found in malignant tissues or cells (Steiner et al, 1997).…”

Downregulation of fibronectin transcription in highly metastatic adenocarcinoma cells

“…1A, b). The extra domain 1 (EDI, also termed EDA) is a FN internal segment encoded by an alternatively spliced exon, characteristic of proliferating cells, but absent from FNs of most resting adult tissues, including plasma FN [22]. In contrast, staining of MM3 primary cultures was completely negative (Fig.…”

Mammary Epithelial-Mesenchymal Interaction Regulates Fibronectin Alternative Splicing via Phosphatidylinositol 3-Kinase

“…Different FN polypeptides arise through an intricate pattern of alternative splicing in three regions of the single primary transcript, (from 5Ј to 3Ј) extra domain II (EDII), extra domain I (EDI), and type III connecting segment (IIICS) (also called EDB or EIIIB, EDA or EIIIA, and V region, respectively), resulting in up to 12 variants in rodents. FN alternative splicing is modulated in a cell type-, development-, and age-specific manner and therefore constitutes a paradigm for studying the regulation of this complex process (2). EDI and EDII are cassette exons, either excluded from or included into the mature FN mRNA.…”