Regulation of Alternative Splicing in Tumor Metastasis
Abstract
Deregulation of pre-mRNA processing has been linked to malignant transformation and the formation of metastases in breast and other cancers. We are studying the role of a group of proteins that contain domains rich in alternating serine and arginine residues (RS domains) in pre-mRNA processing. RS domain proteins comprise members of the "SR family" and "SR-related" proteins, which function in both constitutive and regulated splicing. The past three years of the Idea Award research has identified the SR-related nuclear matrix protein of 160 kDa (SRm160) and the associated oncoprotein DEK as factors that not only associate with splicing complexes, but which also remain bound to mRNA after splicing. Association of these components with mRNA depends on prior splicing, suggesting that SRml60 and DEK are splicing complex proteins which may function in the coupling of splicing with downstream steps in gene expression, including mRNA 3 '-end formation, export, stability and translation. During the final year of research supported by the Idea Award, we have shown that SRm160 participates in mRNA 3 -end formation. Increased levels of SRm 160 stimulates 3 -end cleavage, both in vitro and in vivo. Moreover, SRm 160 was more efficient in promoting the cleavage of splicing-active than splicing-inactive substrates, indicating that it may function in the coupling of splicing and 3 -end formation. These studies have provided the basis for a more detailed understanding of how gene expression processes communicate. Such an understanding is critical if we are to obtain a complete picture of how genetic alterations in breast cancers and other human diseases might impact on the regulation of gene expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADB282194
Entities
People
- Benjamin Blencowe
Organizations
- University of Toronto