The long-term objectives of this research proposal are to define the signaling pathways that regulate hematopoietic progenitor cell survival. Our lab has demonstrated that Bcl-XL is selectively regulated by survival factors, and that this Bcl-2 family member is selectively activated in T-cell and Myeloid malignancies. Preliminary investigations have demonstrated that Jak kinase signaling pathways are both necessary and sufficient for regulation of Bcl-XL, whereas other signaling pathways implicated as regulators of apoptosis, such as Ras, STAT, and PI-3'/Akt kinase pathways, fail to regulate Bcl-XL and are dispensable for cell survival. Additionally, bcl-x and Jak-2 knockouts show marked defects in hematopoiesis pointing towards Bcl-XL and Jak-2 kinase playing critical roles in the programmed cell deaths of hematopoietic progenitors. Both genetic (knockout and knock-in mice) and biochemical (protein levels, promoter regulatory sites, subcellular localization, and post-translational modifications) approaches will be used to determine how the protein levels of Bcl-2 family members are regulated, as well as what regulates their gene expression. These studies will help further our understanding of the regulation of apoptosis in hematopoiesis.
| Baudino, Troy A; Maclean, Kirsteen H; Brennan, Jennifer et al. (2003) Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss. Mol Cell 11:905-14 |
| Zindy, Frederique; Williams, Richard T; Baudino, Troy A et al. (2003) Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci U S A 100:15930-5 |
| Baudino, Troy A; McKay, Catriona; Pendeville-Samain, Helene et al. (2002) c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev 16:2530-43 |
