Expression of Tra2 β in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis

Abstract

The splicing regulator proteins SRSF1 (also known as ASF/SF2) and SRSF3 (also known as SRP20) belong to the SR family of proteins and can be upregulated in cancer. The SRSF1 gene itself is amplified in some cancer cells, and cancer-associated changes in the expression of MYC also increase SRSF1 gene expression. Increased concentrations of SRSF1 protein promote prooncogenic splicing patterns of a number of key regulators of cell growth. Here, we review the evidence that upregulation of the SR-related Tra2 β protein might have a similar role in cancer cells. The TRA2B gene encoding Tra2 β is amplified in particular tumours including those of the lung, ovary, cervix, stomach, head, and neck. Both TRA2B RNA and Tra2 β protein levels are upregulated in breast, cervical, ovarian, and colon cancer, and Tra2 β expression is associated with cancer cell survival. The TRA2B gene is a transcriptional target of the protooncogene ETS-1 which might cause higher levels of expression in some cancer cells which express this transcription factor. Known Tra2 β splicing targets have important roles in cancer cells, where they affect metastasis, proliferation, and cell survival. Tra2 β protein is also known to interact directly with the RBMY protein which is implicated in liver cancer.

Figure 1

Modular structure of the core SR family proteins SRSF1 (also known as ASF/SF2) and SRSF3 (also known as SRp20) and the SR-like protein Tra2β. The RNA recognition motif (RRM) binds to target RNAs, and the RS region is responsible for protein-protein interactions. SRSF1 has a second RRM, annotated ψRRM. SRSF1 and Tra2β have a PP1 docking site.

Figure 2

The (a) TRA2B, (b) SRSF1 (also known as ASF/SF2), and (c) SRSF3 (also known as SRP20) genes are amplified or otherwise mutated in several cancer types. For each of the three genes, data for genetic changes in all cancers were obtained using the cBioPortal database, filtering for percentage of altered cases (studies using mutation data) [22, 23]. The percentage, of cancer samples which showed genetic alterations in large cancer studies are shown on the Y axis and the respective type of cancer on the X axis. Full details of this kind of analysis are given on the cBioPortal website http://www.cbioportal.org/public-portal/index.do.

Figure 3

Protein domain architecture of known Tra2β splicing targets which are expressed in cancer cells. (a) Modular structure of NASP protein assembled from the UniProt database (http://www.uniprot.org/uniprot/P49321) [46], showing the position of the peptide insert encoded by the Tra2β-target exon NASP-T. (b) Modular structure of CD44 protein assembled using information from the UniProt database (http://www.uniprot.org/uniprot/P16070#P16070-6) [46], showing the position of peptide sequences encoded by the Tra2β-target exons CD44 v4 and v5. The CD44 antigen is displayed on the cell surface, and the protein is anchored on the cell surface by a single trans-membrane domain. Alternative isoforms are made through alternative splicing of 10 exons out of 19 encoding amino acids in the extracellular domain and also 2 exons which encode peptide sequence in the cytoplasmic domain. The two exons reported CD44 v4 and v5 exons correspond to amino acids 386–428 and 429–472, respectively, in the encoded protein. The protein domain structures are not drawn to scale.

Figure 4

Hypothetical model suggesting how changes in the cellular environment may influence the expression of Tra2β and lead to downstream changes in mRNA splice isoform production.