TEF-1 is a tissue-specific human transcription factor which binds to and activates transcription from the SV40 early promoter and the HPV-16 E6/E7 promoter and may be involved in regulation of muscle-specific and placenta-specific gene expression. To investigate the mechanism of its tissue-specific expression, we have isolated up to 3 kilobase pairs of 5`-flanking DNA and characterized the promoter of the gene for TEF-1. Multiple transcription start sites centering on a motif similar to the initiator element (Inr) were identified. A minimal promoter, which contains no recognizable TATA element but contains an Inr, delimited at -137 base pairs had full transcriptional activity both in vivo in HeLa cells and in vitro in HeLa cell extracts. This promoter is also highly active in vitro in lymphoid cell extracts, but not in vivo in lymphoid cell lines, which do not express the endogenous TEF-1 gene. The minimal promoter, which is sufficient to direct tissue-specific expression of the TEF-1 gene in vivo, contains multiple sites which bind the ubiquitous transcription factors Sp1 and ATF-1. Mutation of the Inr completely abolished transcription from the major start site while transcription from the minor sites was slightly augmented. Inactivation of the proximal Sp1 site abolished transcription from the principle start site and increased transcription from a 5` minor start site. Insertion of a TATA box element did not qualitatively alter the pattern of start site usage which seemed to be dependent upon integrity of the upstream Sp1 site. These observations suggest a ``cross-talk'' between the Inr and a proximal element to fix transcription start sites, which is independent of spacing and the presence of a TATA element.

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