Differential regulation of human YY1 and caspase 7 promoters by prohibitin through E2F1 and p53 binding sites

Abstract

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.

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

“…A recent study showed that caspase-7 is a p53 responsive gene but the p53-binding site was not identified. 25 In these studies, it was suggested that the caspase-7 gene may bind to p53 through the promoter region within À1000 bp. However, no consensus binding site for p53 was found in this region in the human or mouse caspase-7 gene.…”

Positional and expressive alteration of prohibitin during the induced differentiation of human hepatocarcinoma SMMC-7721 cells

“…Some studies found co-localization between PHB, p53 and E2F1 in the nucleus of breast cancer cells, and demonstrated PHB could activate transcription mediated by p53 and enhance binding of p53 with the promoter. It is also reported that p53-PHB complex translocated from nucleus to cytoplasm after stimulation by the signal of apoptosis [21][22][23] .…”

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

“…Prohibitin 1 (PHB) is a ubiquitously expressed, multifunctional protein implicated in cellular processes including mitochondrial function and protein folding (Nijtmans et al, 2000;Artal-Sanz et al, 2003), proliferation control and suppression of oncogenesis McClung et al, 1995;Dell'Orco et al, 1996), and transcription regulation (Wang et al, 1999Joshi et al, 2007). PHB contains an N-terminal hydrophobic membrane anchoring ␣1-helix domain and a C-terminal leucine/isoleucine-rich motif that acts as a nuclear export signal (Rastogi et al, 2006;Winter et al, 2007).…”