Structural and functional characterization of the upstream regulatory region of the human gene encoding prostate apoptosis response factor-4

Prostate apoptosis response factor-4 (Par-4) is critical to cell growth and apoptosis. Induction of Par-4 expression has been shown to be required for apoptosis in a diversity of cellular systems, including neurons. Neuronal populations in individuals with degenerative disorders show elevated levels of Par-4 protein in advance of cellular and functional loss. To understand the regulation of par-4 expression, we isolated and characterized 5.7 kb of the human par-4 promoter. We demonstrated that the isolated promoter was functional. Similar to the endogenous par-4 gene, par-4 expression could be induced upon apoptotic insult with thapsigargin following introduction of the promoter DNA into human A375 cells. Also, increased levels of the atypical protein kinase C, zetaPKC, was shown to negatively regulate expression from the ectopic par-4 promoter. A 550 bp sequence immediately upstream to the 5'-untranslated region of the gene was found to be responsible for par-4 promoter induction to apoptosis by thapsigargin.