The role of CDCA7/JPO1 in cell proliferation and tumorigenesis

c-Myc is a transcription factor that shows aberrant and elevated expression in many different tumor types. Translocations involving c-Myc are the hallmark of Burkitt's lymphoma, and deregulated Myc expression in cancer cells may contribute to the process of transformation by altering the expression levels of a set of genes that control cell growth and apoptosis, as well as cellular metabolism, adhesion and differentiation. Extensive studies have identified over a thousand targets in the network of Myc responsive genes that may participate in tumorigenesis. The current challenge is to identify those critical target genes that play pivotal roles in Myc-mediated tumorigenesis.; Cancer cells have been shown to generate energy through glycolysis even under aerobic conditions, a phenomenon known as the Warburg effect. The first part of this thesis will focus on the identification of Myc target genes involved in the glycolytic pathway. An analysis of transcript levels of several glycolytic enzymes in Myc overexpressing systems led to the identification of GLUT1, phosphofructokinase and enolase as direct targets of Myc. Our studies suggest that deregulation of Myc may be a major contributor to enhanced tumor glycolysis, in turn conferring a selective growth advantage to tumor cells.; In addition to describing the role that Myc plays in the energy metabolism of tumors, this thesis will also focus on a detailed characterization of the Myc target gene CDCA7/JPO1, a nuclear protein. Previous work in our lab confirmed CDCA7 as a direct Myc target through the use of an inducible Myc system, and showed that its expression is strongly correlated with Myc in all experimental systems that have been examined. The work described in this thesis focuses on (1) the elucidation of the molecular function of CDCA7, (2) the effect of CDCA7 when expressed in a transgenic mouse model, and (3) the description of its expression in human malignancies. These studies reveal that CDCA7 contributes to cell growth and in vivo tumorigenesis, inducing lymphoid and solid tumors in transgenic mice. In studies of human tumors, we show that CDCA7 is highly expressed in lymphomas and leukemias, and may serve as a marker for progression of chronic myelogenous leukemia.