Prolactin in man: a tale of two promoters

Abstract

The pituitary hormone prolactin (PRL) is best known for its role in the regulation of lactation. Recent evidence furthermore indicates PRL is required for normal reproduction in rodents. Here, we report on the insertion of two transposon-like DNA sequences in the human prolactin gene, which together function as an alternative promoter directing extrapituitary PRL expression. Indeed, the transposable elements contain transcription factor binding sites that have been shown to mediate PRL transcription in human uterine decidualised endometrial cells and lymphocytes. We hypothesize that the transposon insertion event has resulted in divergent (pituitary versus extrapituitary) expression of prolactin in primates, and in differential actions of pituitary versus extrapituitary prolactin in lactation versus pregnancy respectively. Importantly, the TE insertion might provide a context for some of the conflicting results obtained in studies of PRL function in mice and man.

Figure 1

Schematic representation of the organisation of the PRL gene. Differential promoter usage results in the transcription of either the short, pituitary, mRNA or the long, extrapituitary, mRNA, containing the extra exon 1a. Since exon 1a is non–coding, both mRNAs give rise to an identical PRL protein. The promoter directing pituitary PRL expression harbours several binding sites for the pituitary^–specific transcription factor Pit–1, which is essential for pituitary PRL expression. The best–described stimulus for extrapituitary PRL expression (in decidua and lymphocytes) is cAMP, which acts via a CRE and several C/EBP sites in the 5′ region flanking exon 1a. The upper panel shows a graphical representation of the conservation (compared to the human sequence) of the chromosome sequence containing the extrapituitary exon 1a (data obtained via the USCS Genome Browser). Notice that exon 1a and part of the 5′ and 3′ flanking intronic sequences are localized within a 498 bp long MER 39 LTR–like sequence, which has the same transcriptional orientation as the gene. Moreover, an additional 198 bp of the 5′ flanking region of exon 1a are provided by a MER20 TE. The MER39 TE is present in human and chimp but not in dog, mouse or rat genomes, whereas theMER20TEis present in human, chimp, dog and rat genomes, but is not detectable in the mouse genome. Interestingly, the transcription factor binding sites that have been shown to mediate extrapituitary PRLexpression are located within the TEs.