Arg-Ser-rich domain-containing proteins (SR proteins), a family of splicing factors, can regulate pre-mRNA alternative splicing in a concentration dependent manner. Thus, the relative expression of various SR proteins may play an important role in alternative splicing regulation. HRS/SRp40, an SR protein and delayed early gene in liver regeneration, can mediate alternative splicing of fibronectin mRNA. Here we determined that transcription of the HRS/SRp40 gene is induced about 5-fold during liver regeneration, similar to the level of steady-state mRNA. We found that both mouse and human HRS promoters lack TATA and CAAT boxes. The mouse promoter region from -130 to -18, which contains highly conserved GA-binding protein (GABP) and YY1 binding sites, conferred high transcriptional activity. While GABPalpha/GABPbeta heterodimer transactivated the HRS promoter, YY1 functioned as a repressor. During liver regeneration, the relative amount of GABPalpha/GABPbeta heterodimer increased 3-fold, and YY1 changed little, which could partially account for the increase in HRS gene transcription. Interleukin-6, a critical mitogenic component of liver regeneration, was able to relieve the repressive activity of the YY1 site within the HRS promoter. The combined effect of small changes in the level of existing transcription factors and mitogenic signals may explain the transcriptional activation of the HRS gene during cell growth.