The factor p8 is a high mobility group (HMG) A family member that is upregulated during the cellular stress response in numerous tissues. Because expression of this protein encourages cellular transformation, our goal is to characterize the mechanism by which the p8 gene is regulated. Using LßT2 cells as a model of a transformed cell in which p8 plays a role in tumor formation, we dissected the p8 promoter into its minimal functional units and found that activating transcription factor 4 (ATF4), a factor also upregulated during cellular stress responses, enhances p8 promoter activity in a dose-dependent manner. In addition, ATF4 binds in the highly conserved major activation domain of the p8 proximal promoter between-130 and-100 bp. Furthermore, we show that six of the nine base pairs that encompass the putative element are essential for ATF4 binding. These findings increase our know ledge of the mechanisms regulating the p8 gene in a genetically defined tumor model.