Mutation of the APC tumor suppressor gene is believed to be a rate-limiting and necessary event in the development of most colorectal tumors, both inherited and sporadic. The APC gene product is a component of the WNT signaling pathway; its ability to interact with the down-regulate beta-catenin affects the expression of genes that are regulated by transcription factors of the TCF/LEF HMG domain family (Clevers and van de Wetering, 1997). Mutation of APC clearly alters the transcription profile of cells through increases in cytoplasmic and nuclear beta-catenin, indirectly activating such genes as c-myc that in turn promote cell growth (He et al., 1998). However, the role of APC in non-beta-catenin induced mechanisms of growth control and differentiation is unknown. Therefore, further functional characterization of APC and its gene product in normal and malignant cells is important for a complete understanding of how its disruption is associated with tumor formation. She has shown that introduction of the APC gene into colon carcinoma cancer cells suppresses tumorigenicity, prevents entry into S-phase of the cell cycle and increases apoptosis, and that baculovirus-expressed, full-length and smaller sections of APC can prevent DNA replication and induce apoptosis using transcriptionally silent in vitro systems. In addition, she has shown that APC is phosphorylated by the cyclin-dependent kinase p34 at M-phase of the cell cycle. She proposes that the APC tumor suppressor contributes to the control of cell growth and cell death independently of beta-catenin-induced transcription. The immediate goals of this proposal are to determine the mechanisms by which APC regulates the cell cycle and apoptosis, and to determine the functional significance of p34-mediated phosphorylation of APC. The long-term goals of this application are to elucidate the mechanisms and pathways through which APC functions and, by doing so, to contribute to the design of therapeutic interventions for the treatments of patients with cancer.
