ALTERNATIVE SPLICING OF FOSB TRANSCRIPTS RESULTS IN DIFFERENTIALLY EXPRESSED MESSENGER-RNAS ENCODING FUNCTIONALLY ANTAGONISTIC PROTEINS

We show that serum-stimulated fibroblasts transiently express two different forms of fosB mRNA, which are generated by alternative splicing of the transcript from a single gene. In addition to the known long form (fosB-L), encoding a protein of 338 amino acids (FosB-L), a second shorter form (fosB-S) with a deletion of 140 bp was detected. This deletion creates a stop codon 3' to the leucine repeat, giving rise to a protein of 237 amino acids (FosB-S) lacking the carboxyl terminus of FosB-L. Only the long FosB form efficiently induces transformation in mouse and rat fibroblast cell lines and trans-represses the c-fos promoter. Both of these functions are suppressed by coexpressed FosB-S. Upon serum stimulation, maximum expression of the oncogenic fosB-L form precedes the expression of the antagonistic fosB-S form, indicating a new mechanism regulating the action of members of the Fos family. However, FosB-L and FosB-S do not differ in all trans-regulatory properties: Trans-activation of a 5x TRE-CAT reporter construct in HeLa and NIH-3T3 cells was found with both FosB forms. These observations suggest a correlation between fosB-induced transformation and trans-repression, thus pointing to different mechanisms involved in transformation by fosB and c-fos/v-fos.