Novel androgen-dependent promoters direct expression of the C4b-binding protein alpha-chain gene in epididymis.

C4b-binding protein (C4BP) is a large plasma protein composed of seven alpha-chains and one beta-chain and is involved in the fluid phase regulation of the classical pathway of the complement system. Complement inhibitory activity is located in the alpha-chain, and its mRNA has been detected only in liver to date. Here, we have isolated cDNA clones encoding the alpha-chain of guinea pig C4BP (C4BP alpha) and have demonstrated significant C4BP alpha mRNA expression in epididymis as well as liver. The level of C4BP alpha transcripts increased in the epididymis after birth, while it remained constant in the liver. C4BP alpha mRNA was also detected in the normal murine epididymis at a significant level, but it decreased drastically after castration, suggesting that epididymal expression of the C4BP alpha gene is regulated by androgen. Gene analysis of guinea pig C4BP alpha indicated that liver and epididymis C4BP alpha mRNA share the coding region and 3'-untranslated region, but are transcribed from independent promoters on a single-copy gene. Two novel epididymis-specific promoters were identified in the region corresponding to the first intron of liver transcripts. The binding motif for hepatocyte NF-1 occurs in the promoter used for transcription of liver C4BP alpha, whereas androgen-responsive elements occur in both promoters used in the epididymis. These findings present a novel link between complement regulators and reproduction. Furthermore, variation in the 5'-untranslated regions, arising from alternative splicing of the newly identified exons, is demonstrable in the guinea pig C4BP alpha transcripts.