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Originally published In Press as doi:10.1074/mcp.M300089-MCP200 on February 15, 2004.
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Molecular & Cellular Proteomics 3:534-547, 2004.
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

The Barrett’s Antigen Anterior Gradient-2 Silences the p53 Transcriptional Response to DNA Damage*

Elizabeth Pohler{ddagger}, Ashley L. Craig{ddagger}, James Cotton{ddagger}, Laura Lawrie§, John F. Dillon{ddagger}, Pete Ross{ddagger}, Neil Kernohan{ddagger} and Ted R. Hupp{ddagger},¶

From the {ddagger} Cancer Research UK Laboratories in the Department of Molecular and Cellular Pathology, University of Dundee, Dundee DD1 9SY, United Kingdom; and § University of Aberdeen, UK Protein Sequencing Facility, Aberdeen AB25 2ZD, United Kingdom

The esophageal 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 overexpressed 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 up-regulated 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 10 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 overexpression of anterior gradient-2 does not alter cell-cycle parameters in unstressed cells, suggesting that this gene is not directly modifying the cell cycle. However, cells overexpressing anterior gradient-2 attenuate p53 phosphorylation at both Ser15 and Ser392 and silence p53 transactivation function in ultraviolet (UV)-damaged cells. Deletion of the C-terminal 10 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 survival factor whose study may shed light on cellular pathways that attenuate the tumor suppressor p53.

To whom correspondence should be addressed: Cancer Research UK Laboratories in the Department of Molecular and Cellular Pathology, University of Dundee, Dundee DD1 9SY, United Kingdom. Tel.: 44-1382-496-430; E-mail: Ted.Hupp{at}cancer.org.uk


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