A major component of all organs is a vascular system that provides a network of capillary vessels for nutrient exchange. The use of irradiation therapy in treatment of many types of cancer results in both immediate and delayed vascular damage that is a consequence of injury to endothelial cells. Damage to the vascular endothelial cells is thus a major cause of complications including, thrombus formation, premature coronary arteriosclerosis, and myocardial infarction, or fibrosis, that occur as a consequence of irradiation therapy. Irradiation results in a decreased expression of anti-coagulant and an increased expression of pro-coagulant factors, such as von Willebrand factor (VWF) in endothelial cells. The circulating VWF molecules in the blood are proposed to be mainly responsible for initial steps of platelet adhesion. Increased VWF expression in response to irradiation results in elevated levels of platelet deposition, which may be a major cause of thrombus formation after irradiation therapy. The formation of platelet thrombi provides a defense mechanism by preserving the vascular integrity after injury, however it can precipitate diseases such as atherosclerosis. A number of irradiation responsive transcription factors have been identified that activate some of the downstream irradiation inducible genes in endothelial cells, however the mechanism of irradiation induction of many other genes including that of VWF is not known. In addition to its major role in development of irradiation induced vascular disease, VWF is a molecule with a highly restricted endothelial specific expression pattern that provides an opportunity to investigate the mechanism of endothelial specific gene regulation in response to irradiation. In our studies, we have found that ionizing radiation results in transcriptional upregulation of VWF.. We have now identified the sequence CCAAT in the VWF promoter as the irradiation responsive cis- acting element. We have also demonstrated that NFY transcription factor interacts with the CCAAT element and mediates the irradiation induced VWF promoter activation. We hypothesize that irradiation results in posttranslational modification of NFY thus increasing its transactivation function. We now propose in specific aim l) to determine the nature of posttranslational modification of NFY in response to irradiation; and in specific aim 2) to determine the molecular mechanism that leads to NFY modification in response to irradiation of endothelial cells.
| Kleinschmidt, Ann M; Nassiri, Marjan; Stitt, Molly S et al. (2008) Sequences in intron 51 of the von Willebrand factor gene target promoter activation to a subset of lung endothelial cells in transgenic mice. J Biol Chem 283:2741-50 |
| Peng, Y; Stewart, D; Li, W et al. (2007) Irradiation modulates association of NF-Y with histone-modifying cofactors PCAF and HDAC. Oncogene 26:7576-83 |
| Wang, Xinyu; Peng, Yiwen; Ma, Yuliang et al. (2004) Histone H1-like protein participates in endothelial cell-specific activation of the von Willebrand factor promoter. Blood 104:1725-32 |
| Peng, Yiwen; Jahroudi, Nadia (2003) The NFY transcription factor inhibits von Willebrand factor promoter activation in non-endothelial cells through recruitment of histone deacetylases. J Biol Chem 278:8385-94 |
