| The protein kinase C (PKC) family of serine-threonine kinases consists of at least 11 known mammalian isoforms with a wide range of tissue distribution, subcellular localization, and molecular functions. First described in 1977 as a cyclic nucleotide-independent protein kinase in rat and bovine brain tissue, it has become apparent that the PKCs are a complex family of multiple isoforms with numerous isotype-specific substrates and functions. One area of biology in which PKC isoforms are known to play critical regulatory roles is that of hematopoietic signaling. However, while distinct roles for individual PKC isoforms in the regulation of hematopoiesis have been identified, a comprehensive analysis of the known family of isoforms during hematopoietic differentiation and proliferation events has not been performed. Within a subset of hematopoietic signaling pathways, several members of the novel subfamily of PKC isoforms have been implicated in mediating signals generated by the myelosuppressive cytokine interferon (IFN). However, one member of this subgroup, PKCeta, has not been evaluated in the context of IFN signaling. Finally, despite a growing number of studies implicating the aberrant expression and/or activity of PKC isoforms in certain malignancies, the expression patterns and potential functional significance of changes in isoform expression have not been comprehensively evaluated in hematopoietic malignancies. Accordingly, the work presented in this thesis aims to expand our knowledge of PKC biology in three critical areas: normal hematopoiesis, IFN signaling, and acute myeloid leukemia. |
