1,4-Galactosyltransferase (4-GT) is a constitutively expressed enzyme that synthesizes the 4-N-acetyllactosamine structure in glycoconjugates. In mammals, 4-GT has been recruited for a second biosynthetic function, the production of lactose which occurs exclusively in the lactating mammary gland. In somatic tissues, the murine 4-GT gene specifies two mRNAs of 4.1 and 3.9 kilobases (kb), as a consequence of initiation at two different start sites 200 base pairs apart. We have proposed that the region upstream of the 4.1-kb start site functions as a housekeeping promoter, while the region adjacent to the 3.9-kb start site functions primarily as a mammary gland-specific promoter (Harduin-Lepers, A., Shaper, J. H., and Shaper, N. L.(1993) J. Biol. Chem. 268, 14348-14359).

Using DNase I footprinting and electrophoretic mobility shift assays, we show that the region immediately upstream of the 4.1-kb start site is occupied mainly by the ubiquitous factor Sp1. In contrast, the region adjacent to the 3.9-kb start site is bound by multiple proteins which include the tissue-restricted factor AP2, a mammary gland-specific form of CTF/NF1, Sp1, as well as a candidate negative regulatory factor that represses transcription from the 3.9-kb start site. These data experimentally support our conclusion that the 3.9-kb start site has been introduced into the mammalian 4-GT gene to accommodate the recruited role of 4-GT in lactose biosynthesis.

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