The role and regulation of the integrin family of cell adhesion molecules has been the major focus of the investigator's laboratory for a number of years. The alpha 2 beta 1 integrin mediates platelet adhesion to collagen in the vessel wall and is required for normal homeostasis. Lack of the alpha 2 beta 1 integrin expression, either due to congenital abnormalities or the development of myelodysplastic/myeloproliferative disorders, is associated with bleeding. In the current funding period, studies have been carried out to understand the regulation of the alpha 2 integrin gene. The investigator identified the 5' flank of the alpha 2 integrin gene, characterized the alpha 2 integrin promoter/enhancers and evaluated the role of megakaryocyte specific and ubiquitous transcription factors in the regulation of the alpha 2 integrin gene expression during normal megakaryocytopoiesis. The investigator plans to complete the characterization of the enhancers and silencers of the alpha 2 integrin gene. She will then alter the course of her studies and evaluate the molecular mechanisms which regulate the alpha 2 beta 1 integrin and another platelet specific integrin, alpha IIb beta 3, following cytokine stimulation. These studies are directed at providing critical data concerning the molecular mechanisms necessary for expression of platelet integrins. Understanding the mechanisms by which TPO and/or other cytokines function may be useful for treatment of myelodysplastic/myeloproliferative disorders and possibly acute megakaryoblastic leukemia.
The aims of the proposal are: 1) to further characterize the defined megakaryocyte enhancer and silencer domains of the alpha 2 integrin gene; 2) to determine the molecular mechanisms by which cytokines regulate megakaryocyte maturation and expression of megakaryocyte/ platelet proteins during differentiation of megakaryoblastic leukemia cells; 3) to establish an in vitro model of hematopoiesis to study megakaryocyte differentiation and the regulation of megakaryocyte specific proteins.
| Zutter, M M; Ryan, E E; Painter, A D (1997) Binding of phosphorylated Sp1 protein to tandem Sp1 binding sites regulates alpha2 integrin gene core promoter activity. Blood 90:678-89 |
| Zutter, M M; Painter, A A; Staatz, W D et al. (1995) Regulation of alpha 2 integrin gene expression in cells with megakaryocytic features: a common theme of three necessary elements. Blood 86:3006-14 |
