PTTG/securin activates expression of p53 and modulates its function

Tariq Hamid,Sham S Kakar

doi:10.1186/1476-4598-3-18

Abstract

BackgroundPituitary 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.ResultsHere 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.ConclusionsOverexpression 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 up-regulates the activity of the bax promoter and increases the expression of bax through modulation of p53 expression.

Highlights

Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed abundantly in most tumors
PTTG upregulates expression of p53 in HEK293 and MCF-7 cells To determine the relationship between PTTG and p53, we first determined the effect of overexpression of PTTG on p53 expression
We used three different cell lines. Two of these HEK293, which is a human embryonic kidney cell line, and MCF-7, which is a human breast cancer cell line, express wild-type p53, and one, PC3, which is a human prostate cancer cell line expresses a mutant form of p53

Summary

Introduction

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. The pituitary tumor transforming gene (PTTG), a securin, was cloned initially from a rat pituitary tumor [1]. PTTG protein is expressed at higher than normal levels in several tumors, including those of the pituitary [4], thyroid [5], colon [6], ovary [7], testis [7] and breast [8], as well as in hematopoietic neoplasms [9]. Overexpression of PTTG enhances cell proliferation, induces cellular transformation, and promotes tumor formation in nude (page number not for citation purposes). The involvement of PTTG in several cellular functions, such as mitosis [14,15], cell cycle progression [16], DNA repair [17] and secretion and expression of basic fibroblast growth factor (bFGF) [18] and vascular endothelial growth factor (VEGF) [19] has been reported

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