EGR-1/TIS8 is a primary response gene that encodes a zinc finger containing protein and is induced in a number of cell types by a variety of ligands. We have isolated and mapped the human EGR-1/TIS8 gene and sequenced the 5'upstream flanking region. A'TATA'homology and several putative regulatory elements, including two Sp1 sites, five serum response-like elements, two cAMP response-like elements, an EGR-1 binding site (EBS), and a tetra-decanoyl phorbol acetate (TPA)-responsive element have been identified within 700 nucleotides of the upstream region. We demonstrated that a 500-base pair fragment, which includes several of these possible regulatory sequences, is functional and responsive to TPA in transient transfection assays. A further understanding of the regulation and function of human EGR-1/TIS8 gene expression may provide insight into the mechanisms that control normal and neoplastic proliferation of human cells.