Transcriptional activation of p53 by Pitx1.

ABSTRACT

Little is known about factors that stimulate transcription of the p53 tumor suppressor gene. Here, we report that the human pituitary homeobox 1 (hPitx1) transcription factor increases the expression of p53 at the mRNA and protein levels in human mammary carcinoma (MCF-7) cells. Increased p53 mRNA expression was due to activation of the p53 promoter by hPitx1. hPitx1 bound directly to the p53 promoter and functionally utilized two hPitx1 consensus elements. The predominant consensus element utilized by hPitx1 to stimulate p53 transcription was located within the first exon of the p53 gene. A hPitx1 mutant (hPitx1-R141P) acting as a dominant inhibitor repressed p53 transcription. Forced expression of hPitx1 resulted in cell-cycle arrest and p53-dependent apoptosis in p53-replete MCF-7 cells. Furthermore, hPitx1 stimulated the transcription of p53 target genes involved in cell-cycle arrest and apoptosis (p21 and PTGF-beta), again in a p53-dependent manner. Depletion of endogenous hPitx1 by small interfering RNA (siRNA) in MCF-7 cells resulted in decreased basal expression of p53 and consequently of p21 and placental transforming growth factor beta (PTGF-beta). Depletion of p53 by siRNA dramatically attenuated hPitx1-induced apoptosis in MCF-7 cells. Thus, p53 is a direct transcriptional target gene of hPitx1. This observation is concordant with the recent identification of hPitx1 as a tumor suppressor gene.