Splicing Factor Tra2-β1 Is Specifically Induced in Breast Cancer and Regulates Alternative Splicing of theCD44Gene

Abstract

The human CD44 gene undergoes extensive alternative splicing of multiple variable exons positioned in a cassette in the middle of the gene. Expression of alternative exons is often restricted to certain tissues and could be associated with tumor progression and metastasis of several human malignancies, including breast cancer. Exon v4 contains multiple copies of a C/A-rich exon enhancer sequence required for optimal inclusion of the exon and binding to the nucleic acid-binding proteins YB-1 and human Tra2-B1. Here, we show that hTra2-B1, a member of the extended family of serine/arginine-rich (SR) splicing factors, enhances the in vivo inclusion of CD44 exons v4 and v5. It increased inclusion of exons v4 and v5 and acted synergistically with YB-1. Activation required the C/A-rich enhancer within exon v4. Several other SR proteins had none or only a slight effect on CD44 exon inclusion. In contrast, SC35 inhibited exon usage and antagonized the effects of Tra2 or YB-1. In a matched pair analysis of human breast cancers and their corresponding nonpathologic tissue controls, we found a significant induction of Tra2-B1 in invasive breast cancer, both on the RNA and protein levels. Together with our functional data, these results suggest an important role for Tra2-B1 in breast cancer. Induction of this splicing factor might be responsible for splicing of CD44 isoforms associated with tumor progression and metastasis. (Cancer Res 2006; 66(9): 4774-80)

Expression levels of hnRNP G and hTra2‐beta1 correlate with opposite outcomes in endometrial cancer biology

“…Our data are in line with recent findings of our group, showing that over-expression of hTra2-beta1 in breast and cervical cancer has been detected as well as an association of this induction to a poor patient outcome. 23,36 Unlike nuclear hTra2-beta1, within the groups of tumors with positive cytoplasmic staining, higher hTra2-beta1 displayed a better disease-specific survival. This phenomenon indicates, for our understanding, that not only the amount but also the localization or distribution of splicing factors influences tumor biology.…”

“…21 CD44, ESRa, BRCA1, scr, Her2/neu are such genes regulated by hTra2-beta1, which play important roles especially in hormone-dependent malignancies such as breast and ovarian cancer. 6,23 So far, mechanism of these two factors influencing cancer biology remains unknown. Nasim et al 25 proposed that the ratio of hnRNP G/hTra2-beta1 influenced cellular splicing preference.…”

“…[20][21][22] An increasing number of human hormone-dependent cancers including breast and ovarian cancer demonstrated pathologically induced expression levels of hTra2-beta1. 6,23 Yeast twohybrid screens and consecutive functional studies revealed that hnRNP G and hTra2-beta1 interact with each other, 24 and they exert antagonizing effects on alternative splicing with opposite splicing preference on human a s -tropomyosin gene as well as opposite consequences of mRNA processing of dystrophin pseudo-exon in muscle tissue. 25 In our study, we investigated the potential association of hnRNP G and hTra2-beta1 with clinicopathological parameters of EC and consecutively their impact on clinical outcome of both subtypes of EC.…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Aberrant processing of mRNAs in tumor cells has been described for the MDM2, RasGRP4, SLP-65, TLE1, TLE4, MTA1 and CD44 genes and is emerging as an important characteristic of tumor cells (Bartel et al, 2002;Kumar et al, 2002;Reuther et al, 2002;Yang et al, 2002;Jumaa et al, 2003;Venables, 2004;Watermann et al, 2006) and is observed in other diseases, such as myotonic dystrophy (Charlet-B et al, 2002). In aberrant splicing, portions of exons, portions of introns or both are retained within transcripts that fail to be purged by the cellular pathways designed to scavenge abnormal mRNAs, such as nonsense-mediated decay (Culbertson, 1999;Wilkinson and Shyu, 2002).…”

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…12,13 Tra2β also facilitates alternative splicing of the CD44 gene via binding to CD44 exons v4 and v5, which is associated with breast cancer progression. 14,15 Alternative splicing is regulated in a developmental stage-or tissue-specific manner. 3 As Tra2β-deficient mice resulted in early embryonic lethality around E7.5, Tra2β-mediated regulation of alternative splicing was considered to be essential for mouse embryogenesis and spermatogenesis.…”