(from the application): Our overall objective is to understand the regulatory mechanisms that control the growth and differentiation of hematopoietic cells in order to understand how oncoproteins subvert these mechanisms to cause leukemia. In this proposal the oncoprotein under study is the v-Ski oncoprotein, which has been demonstrated to cooperate with tyrosine kinases to cause leukemia. Recently the Ski protein has been shown to play a regulatory role in several signal transduction pathways that are frequent targets for mutagenesis in human tumors. Ski interacts with the retinoblastoma protein, (Rb), and effects E2F regulated transcription. It also represses transcription induced by retinoic acid (RA) and by transforming growth factor beta (TGFb). In vitro transformation by Ski is a consequence of over-expression of the Ski protein. This leads to the hypothesis that Ski transforms cells by interacting with complexes involved in signaling by Rb, RA and TGFb and either sequesters important components or disrupts the normal regulatory equilibrium. In vivo Ski plays a role in the causation of hematopoietic stem cell leukemia and mice genetically null for the Ski gene have severe defects in hematopoiesis. These data indicate that Ski plays an important regulatory role in hematopoietic cell growth and differentiation and that these regulatory interactions are important for both normal and malignant hematopoiesis. Our objective is to dissect the role Ski plays in these regulatory pathways and determine how Ski contributes to the causation of hematopoietic malignancies.
Our specific aims are: 1. To perform both a genetic and functional analysis of the role of Ski in signaling by nuclear hormone receptors, Rb and TGFb. 2. To dissect the interaction of Ski with the various signaling pathways in hematopoietic cell growth and leukemogenesis. 3. To perform a genetic and functional analysis of the Ski-interacting protein, Skip in the same signaling pathways analyzed for Ski in Aim 1.
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