Non-killer cell-specific transcription factors silence the perforin promoter

Perforin is a pore-forming killer protein exclusively expressed by cells functionally defined as cytolytic lymphocytes. Previous reporter gene investigations have indicated that the cell-type-specific expression of the perforin gene is determined by the promoter and upstream region but the respective cis- and trans-acting molecules remain to be identified. In this investigation, we differentially display DNA-protein interactions of perforin-positive vs perforin-negative cell types and functionally test their biological relevance. Our results provide molecular evidence for the transcriptional repression of the perforin gene in non-killer cells by two novel regulatory elements. One of the respective transcription factors that are exclusively expressed by non-killer cells appears to be an Ets family member. Thus, the development of cells expressing perforin, and perhaps cytolytic lymphocytes in general, may involve a shutdown of the genes for these proteins.