Identification and characterization of cis elements in the STAT3 gene regulating STAT3 alpha and STAT3 beta messenger RNA splicing

Signal transducer and activator of transcription 3 (STAT3) is an oncogene a nd a critical regulator of multiple cell-fate decisions, including myeloid cell differentiation. Two isoforms of STAT3 have been identified: alpha (p9 2) and beta (p83). These differ structurally in their C-terminal transactiv ation domains, resulting in distinct functional activities. The cis genetic elements that regulate the ratio of alpha to beta messenger RNA (mRNA) are unknown. In this study, cloning, sequencing, and splicing analysis of the human and murine STAT3 genes revealed a highly conserved 5' donor site for generation of both alpha and beta mRNA and distinct branch-point sequences, polypyrimidine tracts, and 3' acceptor sites (ASS) for each. The beta 3' A S was found to be located 50 nucleotides downstream of the alpha 3' AS in e xon 23. Two additional cryptic 3' ASs (delta and epsilon) were also identif ied. Thus, we identified for the first time the cis regulatory sequences re sponsible for generation of STAT3 alpha, and STAT3 beta mRNA. (C) 2001 by T he American Society of Hematology.