RNA binding protein CUGBP2/ETR-3 regulates STAT3 alternative splicing

Signal transducer and activator of transcription 3 (STAT3) is a multifactorial regulator involved in many biological responses. Alternative splicing of STAT3 pre-mRNA leads to an internal 50-nucleotide deletion of exon 23 selecting an alternative 3' acceptor site, resulting in the generation of two splicing isoforms, STAT3 alpha and STAT3 beta. STAT3 beta lacks 55 amino acid-residue transactivation domain at the C-terminal of STAT3 alpha replacing seven unique amino acids. Although STAT3 beta was originally thought to be a dominant negative isoform of STAT3 alpha, accumulating evidence have shown that STAT3 beta possesses both its unique functions and those that overlap with STAT3 alpha in fundamental cellular processes. However, much remains unknown about STAT3 premRNA alternative splicing in determining the balance between STAT3 isoforms. In this study, we identified cis-regulatory elements and CUGBP2/ETR-3 as a novel trans-acting factor that regulates STAT3 alternative splicing. Our findings demonstrate that STAT3 splicing can be modulated by CUGBP2 via association with UGrich elements of intron 22, providing a novel insight into the mechanism of STAT3 alternative splicing. CUGBP2 would be a crucial molecule regulating the balance of STAT3 isoform expression, thus targeting CUGBP2 and its recognition sequences in intron 22 of STAT3 might impact on various biological processes regulated by STAT3 signaling pathway.