CD30, as a member of the tumor necrosis factor (TNF) receptor family, is expressed on the surface of activated lymphoid cells. CD30 overexpression is a characteristic of lymphoproliferative diseases such as Hodgkin's/non-Hodgkin's lymphomas, embryonal carcinoma, and a number of Th2-associated diseases. The CD30 gene has been mapped to a region of the murine genome that is involved in susceptibility to systemic lupus erythematosus, Functionally, CD30 may play a role in the deletion of autoreactive T cells. We were interested in determining the molecular nature of CD30 overexpression. Sequence comparison has revealed significant identity between the TATA-less human and murine CD30 promoters; they share a number of common consensus binding moths. Transfection assays identified three regions of transcriptional importance; the region between position -1.2 kb and -336 bp, containing a CCAT microsatellite sequence, a conserved Spl site at positions -43 to -38, and a downstream promoter element (DPE) at positions +24 to +29. EMSA and. DNase I footprinting showed specific DNA-protein interactions of the CD30 promoter with the Spl site and the CCAT repeat region. The DPE element was shown to be essential for start site selection. We conclude that the conserved Spl site at -43 to -38 is associated with maximum reporter gene activity, the DPE element is required for start site selection, and the CCAT tetranucleotide repeats act to repress transcription. We also have shown that the microsatellite is multiallelic, when we screened a random healthy population. Further studies are required to determine whether microsatellite instability in the repressor predisposes susceptible individuals to CD30 overexpression.