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Physical and functional interaction of p53 and p110α and implications in ovarian carcinogenesis

University of British Columbia

In approximately 40% of ovarian cancers, PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is amplified. This amplification correlates with increased PIK3CA transcription, p110α protein expression, and PI3K activity. Moreover, PIK3CA is implicated as an oncogene in ovarian cancers. Another common mutation in ovarian cancer leads to loss of p53 function. Alterations to p53 are known to be involved in tumour development and progression. Previous studies have shown that in benign cells, the p53 and PI3K pathways are connected through the regulation of PTEN by p53. Therefore, in the presence of p53, PTEN levels increase and exert their effect through decreasing P-AKT levels, and thereby pro-survival activities. In addition, it has been suggested that in cancer cells, p53 down-regulates the pro-survival pathway, independent of PTEN, by negatively regulating p110α levels. However, it has not been shown whether the p53 effect on p110α levels is direct or indirect and whether this interaction exists in benign cells. Our studies show, for the first time, a direct relationship between p53 and PI3K pathways. We used temperature sensitive cells, in which p53 function was regulated through the shift in temperature. We showed that p53 negatively regulates PIK3CA transcript and p110α levels through direct binding to the PIK3CA promoter. Moreover, we determined that the regulation of p110α levels by p53 is also present in ovarian cancer cells where overexpression of p53 significantly reduced p110α levels. In addition, for the first time, we identified two alternate promoters (promoter la and promoter lb) upstream of two alternate first exons (exonla and exonlb) that transcribe into two alternate transcripts with different 5' untranslated regions (5' UTRs). Our results determined direct binding of p53 to PIK3CA promoter la, and studies to determine whether this direct binding is responsible for the suppression of the promoter and the down-regulation of PIK3CA transcript and p110α levels are currently in progress. Our studies suggest that the loss of p53 in ovarian cancers may result in loss of transcription suppression of PIK3CA and therefore increased p110α levels and PI3K activity, which may in turn lead to increase in proliferation and resistance to apoptosis.

Text

2009-12-11

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http://hdl.handle.net/2429/16421

Reproductive and Developmental Sciences

University of British Columbia

UBCV

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