Our objective is to understand the regulatory mechanisms that control the proliferation, differentiation and apoptosis of cells and how oncoproteins subvert these mechanisms to cause cancer. One of our projects is on growth factor receptor tyrosine kinases (RTK) that have been implicated in the development of leukemia and colon cancer. The Sea/Stk/Ron receptor has been implicated in the development of erythroid leukemia, and colon cancer. Cancer involves the loss of regulatory mechanisms that control the balance between cell growth, apoptosis and differentiation. Based on precedent RTKs have the potential to affect all three of these regulatory mechanisms. The aim of our research is to determine: (i), which regulatory events are disrupted by the Sea/Stk/Ron receptors: (ii) to identify the contributions of the various downstream signaling cascades in these events.
Our other interest is in the Ski oncogene which encodes a nuclear protein. Recently the Ski protein has been shown to play regulatory roles in various signal transduction pathways that are frequent targets for mutagenesis in human tumors. Ski has been shown to interact with the retinoblastoma protein, (Rb), and effect E2F regulated transcription. It has been shown to repress 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 is transforming cells by interacting with the complexes that are involved in signaling by Rb, RA and TGFb, either sequestering important components or disrupting the normal regulatory equilibrium. In vivo the only oncogenic property of Ski demonstrated to date is the ability to play a role in the causation of hematopoietic stem cell leukemia, however to do this it also needs cooperating signals from RTKs such as Sea. These data indicate that Ski plays important regulatory roles in signal transduction pathways that control 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 as well as other malignancies.