Prohibitin is a 30 kDa growth suppressive protein that has pleiotropic functions in the cell. Although prohibitin has been demonstrated to have potent transcriptional regulatory functions, it has also been proposed to facilitate protein folding in the mitochondria and promote cell migration in association with Raf-1. Our previous studies have shown that prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, prohibitin could bind to and enhance the transcriptional activity of p53. Here, we show that promoters of human YY1 (Yin and Yang 1) as well as caspase 7 genes are modulated by prohibitin. YY1 promoter activity was reduced upon overexpression of prohibitin, while it was enhanced when prohibitin was depleted by small interfering RNA techniques. The repressive effects of prohibitin on the YY1 promoter were mediated through E2F binding sites, as seen by mutational analysis and chromatin immunoprecipitation assays. Further, depletion of E2F1 prevented prohibitin from repressing the YY1 promoter. In contrast with YY1, prohibitin overexpression led to enhanced levels of caspase 7, whereas depletion of prohibitin reduced it. Interestingly, the caspase 7 promoter was found to have p53-binding sites and prohibitin activated this promoter through p53. These studies show that prohibitin can have diverse effects on the expression of different genes and the activity of various cellular promoters is affected by prohibitin. Further, it appears very likely that prohibitin carries out many of its cellular functions by affecting the transcription of different genes.