Ras proteins are crucial regulators of cell proliferation, survival and differentiation. Aberrant activation of Ras proteins, either by Ras mutations or by altering genes that directly or indirectly regulate Ras, is common in both solid tumors and hematologic malignancies. Ras proteins can interact with a wide spectrum of Ras effectors that play either positive or negative roles in the control of cell proliferation and survival. The association with different microdomains of the plasma membrane as well as other internal cell membranes may allow different Ras proteins to access to different pools of Ras effectors and to generate distinct signal outputs. In the past, laboratory studies of the roles of Ras effectors in oncogenesis have been performed mostly in cultured cells. And even in these assays, cellular transformation of different cell types was shown to require different Ras effectors. Leukemogenesis is a complex process that not only involves the effects of oncogenic mutation(s) within the target cells, but interactions of such cells with the rest of the in vivo environment. The overall hypothesis of this proposal is that the in vivo leukemogenesis by oncogenic Ras may involve unique Ras signaling networks. We have previously examined the leukemogenicity of oncogenic N-Ras using an improved mouse bone marrow transduction and transplantation model and found that oncogenic N-Ras efficiently induced myeloproliferative disorder and acute myelogenous leukemia-like disease in mice. We will use this mouse model to test the hypothesis stated above by examining the roles of various post-translational modifications and effectors of Ras in N-Ras leukemogenesis.
The specific aims for this proposal are: 1. To determine the roles of post-translational modifications of N-Ras in leukemogenesis by a mutational analysis of the modification sites of oncogenic N-Ras, as well as by analyzing N-Ras leukemogenesis in mice with conditional knockout alleles of Reel or Icmt (genes encoding the Ras converting enzyme and isoprenylcysteine carboxyl methyltransferase, respectively). 2. To determine the roles of downstream effectors of Ras in N-Ras leukemogenesis by a combination of biological and biochemical approaches, using effector domain mutants of the oncogenic N-Ras, as well as activated and inhibitory forms of various effectors of Ras. The ultimate goal of these studies is to identify critical molecular events in Ras leukemogenesis, allowing therapeutic interventions of leukemias involving Ras.
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