PTTG/securin activates expression of p53 and modulates its function

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Abstract
Background: Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed abundantly in most tumors. Overexpression of PTTG induces cellular transformation and promotes tumor formation in nude mice. PTTG has been implicated in various cellular processes including sister chromatid separation during cell division as well as induction of apoptosis through p53-dependent and p53-independent mechanisms. The relationship between PTTG and p53 remains unclear, however. Results: Here we report the effects of overexpression of PTTG on the expression and function of p53. Our results indicate that overexpression of PTTG regulates the expression of the p53 gene at both the transcriptional and translational levels and that this ability of PTTG to activate the expression of p53 gene is dependent upon the p53 status of the cell. Deletion analysis of the p53 gene promoter revealed that only a small region of the p53 gene promoter is required for its activation by PTTG and further indicated that the activation of p53 gene by PTTG is an indirect effect that is mediated through the regulation of the expression of c-myc, which then interacts with the p53 gene promoter. Our results also indicate that overexpression of PTTG stimulates expression of the Bax gene, one of the known downstream targets of p53, and induces apoptosis in a human embryonic kidney cell line (HEK293). This stimulation of bax expression by PTTG is indirect and is mediated through modulation of p53 gene expression. Conclusions: Overexpression of PTTG activates the expression of p53 and modulates its function, with this action of PTTG being mediated through the regulation of c-myc expression. PTTG also upregulates the activity of the bax promoter and increases the expression of bax through modulation of p53 expression.