Recent advances in cell biology have shown the integrins to be adhesive and signaling receptors responsive to alterations in the extracellula environment. The hypothesis to be tested is that ionizing radiation activates the a 6b 4 integrin. The integrin activation occurs by oxidation of the external tryptophan residues and results in a phosphotyrosine signal on the cytoplasmic face of the b 4 subunit. The integrin signal increases the transactivation of genes as a damage response.
The specific aims are: 1. Determine if tryptophan oxidation or an alteration of the tyrosine phosphorylation state of the a 6b 4 integrin occurs in response to ionizing radiation. 2. Determine if inactivating a 6b 4 constructs will block the radiation induced signaling cascade. The b 4 integrin has an extensive cytoplasmic domain which contains the tyrosine activation motif (TAM). Constructs of theb 4 integrin with the cytoplasmic portion deleted and/or TAM deleted will be tested for their ability to signal with ionizing radiation. 3. Determine if the activation of the integrin can be blocked by excess of the natural or synthetic ligand of the integrin. The natural ligand for a 6b 4 is laminin 5. This will be used to test whether the signaling can be attenuated b engagement of the a 6b 4 integrin with its ligand or clustering of the receptor. Alternatively, synthetic peptides which interact with the a 6b 4 integrin will be tested as agonists. 4. Determine if the a 6b 4 activation by ionizing radiation results in the induction of transcription of a reporter gene. We will use the constructs of the a 6b 4 integrin and the use of a pGL2-reporter vector system utilizing the luciferase gene to test the dependence of the transcription response for the signaling portion of the b 4 integrin. The proposed work will add to our current knowledge of cellular signaling of a radiation damage response, basic integrin biology and suggested ways in which to increase the efficacy of the radiation treatment of a 6b 4 expressing epithelial cancers.
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