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Current Chemical Biology


ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

The Anterior Gradient-2 Pathway as a Model for Developing Peptide-Aptamer Anti-Cancer Drug Leads that Stimulate p53 Function

Author(s): Argyro Fourtouna, Euan Murray, Judith Nicholson, Magdalena M. Maslon, Lisa Y. Pang, David T.F. Dryden and Ted R. Hupp

Volume 3, Issue 2, 2009

Page: [124 - 137] Pages: 14

DOI: 10.2174/2212796810903020124

Price: $65


Oncogenic inhibition of the p53 tumour suppressor is a key feature of human cancer. However, relatively few oncogenic drug targets which inhibit p53 have been identified using a variety of model systems. As a prototype, a clinical proteomics screen was initiated in preneoplastic disease where selection pressures were placed on p53 gene mutation to identify clinically relevant and novel p53 inhibitors. This screen identified a protein named Anterior Gradient-2 (AGR2) as a novel type of p53 inhibitor. As reactivation of p53 holds promise as a therapeutic strategy for cancer treatment, AGR2 still requires validation as an anti-cancer drug target. Many signalling proteins function by binding to linear domains and combinatorial peptide libraries facilitate lead identification for validating a potential drug target. The AGR2 protein localized in the endoplasmic reticulum and nuclear compartments and this distribution was mediated by a Cterminal KTEL sequence. The transfection of AGR2 into cells stimulated p53 protein accumulation in the cytosol forming a novel assay for measuring AGR2-mediated inhibition of p53. Optimized AGR2-binding penta-peptide aptamers were minimized using substitution mutagenesis. Transfection of EGFP-peptide-aptamers containing the core TxIYY pentapeptide sequence stabilized p53 and increased its nuclear localization. The fusion of the TxIYY penta-peptide to the cell membrane permeable antennapedia peptide also resulted in a similar nuclear relocalization of p53 protein. These data indicate that the AGR2 pathway can be targeted with peptide-aptamers resulting in p53 stabilization and highlight the utility of linking clinical proteomics to combinatorial peptide chemistry to rapidly discover and validate uncharacterized proteins as potential anti-cancer drug targets.

Keywords: Cancer, p53, Anterior Gradient-2, aptamers, therapeutics

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