Integrins are cell adhesion and signaling receptors responsive to alterations in the extracellular environment. In the previous three year grant, our objective was to determine whether ionizing radiation activates the A6 integrin resulting in a phosphotyrosine signal and to determine whether this can be influenced by the natural or synthetic ligands. Our results show that the A6 integrin is activated in response to irradiation and that ionizing radiation will activate A6 integrin containing adhesion sites. The integrin linked kinase (ILK) is implicated as a downstream signaling event since a corresponding Akt/PKB phosphorylation is detected. The extracellular matrix ligands influence the response. In addition, a phosphotyrosine signal within the adhesion site located on paxillin is detected. We propose to extend these studies with the following aims: 1. Determine if the mechanism of IR signaling involves integrin linked kinase (ILK) activation. 2. Determine if focal adhesion site proteins are essential to the IR generated signal. 3. Determine if the extracellular domain of the A6 integrin (containing the beta barrel domain) or a specific splice variant of the B1 integrin is essential to the phosphorylation signals. 4. Determine if anti-adhesion peptides or natural ligands will alter the IR signal. The proposed work will add to our current knowledge of cellular signaling of a radiation damage response, basic integrin biology and suggest ways to increase the efficacy of the radiation treatment of A6 integrin expressing epithelial cancers.
| Warters, Raymond L; Gaffney, David K; Kramer, Gwen F et al. (2009) Transient dephosphorylation of p53 serine 376 as an early response to ionizing radiation. Radiat Res 171:725-34 |
| Demetriou, Manolis C; Kwei, Kevin A; Powell, Marianne B et al. (2008) Integrin A6 Cleavage in Mouse Skin Tumors. Open Cancer J 2:1-4 |
| Pawar, Sangita C; Dougherty, Shona; Pennington, Michael E et al. (2007) alpha6 integrin cleavage: sensitizing human prostate cancer to ionizing radiation. Int J Radiat Biol 83:761-7 |
| Pawar, Sangita C; Demetriou, Manolis C; Nagle, Raymond B et al. (2007) Integrin alpha6 cleavage: a novel modification to modulate cell migration. Exp Cell Res 313:1080-9 |
| Sroka, Thomas C; Pennington, Michael E; Cress, Anne E (2006) Synthetic D-amino acid peptide inhibits tumor cell motility on laminin-5. Carcinogenesis 27:1748-57 |
| Kremer, Celeste L; Schmelz, Monika; Cress, Anne E (2006) Integrin-dependent amplification of the G2 arrest induced by ionizing radiation. Prostate 66:88-96 |
| Sroka, Thomas C; Marik, Jan; Pennington, Michael E et al. (2006) The minimum element of a synthetic peptide required to block prostate tumor cell migration. Cancer Biol Ther 5:1556-62 |
| Schmelz, Monika; Moll, Roland; Hesse, Ulrike et al. (2005) Identification of a stem cell candidate in the normal human prostate gland. Eur J Cell Biol 84:341-54 |
| Oshiro, Marc M; Futscher, Bernard W; Lisberg, Aaron et al. (2005) Epigenetic regulation of the cell type-specific gene 14-3-3sigma. Neoplasia 7:799-808 |
| Oshiro, Marc M; Kim, Christina J; Wozniak, Ryan J et al. (2005) Epigenetic silencing of DSC3 is a common event in human breast cancer. Breast Cancer Res 7:R669-80 |
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