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Submitted on September 2, 2003
Revised on February 13, 2004
Accepted on February 15, 2004

The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage

Elizabeth Pohler, Ashley Craig, James Cotton, Laura Lawrie, John F. Dillon, Peter Ross, Neil Kernohan, and Ted R. Hupp

Molecular and cellular Pathology, University of Dundee, Dundee, Scotland DD1 9SY

Corresponding Author: t.r.hupp{at}dundee.ac.uk

The oesophageal epithelium is subject to damage from bile acid reflux that promotes normal tissue injury resulting in the development of Barrett’s epithelium. There is a selection pressure for mutating p53 in this preneoplastic epithelium thus identifying a physiologically-relevant model for discovering novel regulators of the p53 pathway. Proteomic technologies were used to identify such p53 regulatory factors by identifying proteins that were over-expressed in Barrett’s epithelium. A very abundant polypeptide selectively expressed in Barrett’s epithelium was identified as Anterior Gradient-2. Immunochemical methods confirmed that Anterior Gradient-2 is universally upregulated in Barrett’s epithelium, relative to normal squamous tissue derived from the same patient. Transfection of the Anterior Gradient-2 gene into cells enhances colony formation, similar to mutant oncogenic p53 encoded by the HIS175 allele, suggesting that Anterior Gradient-2 can function as a survival factor. Deletion of the C-terminal ten amino acids of Anterior Gradient-2 neutralizes the colony enhancing activity of the gene, suggesting a key role for this domain in enhancing cell survival. Constitutive over-expression of Anterior Gradient-2 does not effect cell cycle parameters in unstressed cells, suggesting that this gene is not directly modifying the cell cycle. However, cells over-expressing Anterior Gradient-2 attenuate p53 phosphorylation at both Ser15 and Ser392 and silence p53 transactivation function in UV damaged cells. Deletion of the C-terminal ten amino acids of Anterior Gradient-2 permits phosphorylation at Ser15 in UV damaged cells, suggesting that the C-terminal motif promoting colony survival also contributes to suppression of the Ser15 Kinase pathway. These data identify Anterior Gradient-2 as a novel, clinically relevant factor that inhibits the tumour suppressor p53 and whose study may shed light on mechanisms of cancer progression.


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