Inhibition of Cyclooxygenase-2 Gene Expression by p53

Abstract

Oncogenes enhance the expression of cyclooxygenase (Cox)-2, but interactions between tumor suppressor genes and Cox-2 have not been studied. In the present work, we have compared the levels of Cox-2 and the production of prostaglandin E 2 in mouse embryo fibroblasts that do not express any p53 ((10)1) versus the same cell line ((10.1)Val5) engineered to overexpress wildtype (wt) p53 at 32°C or mutant p53 at 39°C. Cells expressing wt p53 showed about a 10-fold decrease in synthesis of prostaglandin E 2 compared with those expressing mutant p53. Levels of Cox-2 protein and mRNA were markedly suppressed by wt p53 but not by mutant p53. Nuclear run-offs revealed decreased rates of Cox-2 transcription in cells expressing wt p53. The activity of the Cox-2 promoter was reduced by 85% in cells expressing wt p53 but was reduced only by 30% in cells expressing mutant p53 compared with cells null for p53. The effect of p53 on the suppression of Cox-2 promoter activity was localized to the first 40 base pairs 5 from the transcription start site. Electrophoretic mobility shift assay revealed that p53 competed with TATA-binding protein for binding to mouse Cox-2 or human Cox-2 promoter extending from ؊50 to ؉52 base pairs. The results of this study suggest that interactions between p53 and Cox-2 could be important for understanding why levels of Cox-2 are undetectable in normal cells and increased in many tumors.

Transcriptional regulation by p53: one protein, many possibilities

“…With respect to Pol II inhibition, several mechanisms have been documented (Figure 3). These include repression of transcription activators by physical interaction with and preventing them from activating the promoter [111][112][113][114][115][116] or by displacing them from the adjusting or overlapping binding sites within the promoter, [117][118][119][120] interference with the assembly of transcription machinery, 7,121 repression through the recruitment of histone deacetylase (HDAC) and, possibly, other chromatin modifying factors, [122][123][124] and finally through novel REs with the unique architecture that dictates the outcome of p53 binding. 14,125 Combination of two of the above mechanisms has been also documented.…”

Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB

“…In 1999, Subbaramaiah et al (1999) reported that expression of p53 at high levels in mouse fibroblasts repressed Cox-2, and proposed that p53 may compete with TATAbinding proteins for binding to the COX-2 promoter. More recently, Han et al (2002) demonstrated an opposite effect, with namely a physiological, p53-dependent increase in Cox-2 expression in response to DNA damage.…”

Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma

“…While some studies demonstrate that wild-type p53 overexpression leads to increased COX-2 levels (Han et al, 2002;Corcoran et al, 2005), other studies report opposite effects where p53 inhibits COX-2 transcription (Subbaramaiah et al, 1999;Liu et al, 2005). However, there is general agreement in the literature regarding the effect of COX-2 on p53 activity.…”