ZPK (zipper protein kinase)/MUK/DLK/MAP3K12, a member of mixed-lineage kinases (MLKs), is expressed in a tissue-specific manner, particularly in developing brain, and likely to contribute to cytodifferentiation, apoptotic elimination, and migration. To understand the preferential expression of ZPK in neuronal tissues, we have analyzed the putative core promoter region upstream of the first exon of the human ZPK gene. The core promoter region is TATA-less, but contains several potential transcription factor-binding motifs such as a GC-box, all of which are well conserved between human and mouse. Reporter assays and 'gel-shift' analysis using SH-SY5Y cells revealed that a xenobiotic responsive element (XRE)-like motif (GGGCGTGTCC) was preferentially recognized by Sp3, and enhanced the core promoter activity. However, the core promoter activity was still potent even in HeLa cells which barely express ZPK. Our results suggest that, for the selective expression of ZPK gene, cell-specific negative regulatory element(s) which locate outside of the core promoter region repress the potent basic promoter activity.