简介

Our major research interests concern how mammalian cell growth and cell cycle are regulated, and how misregulation, particularly of transcription factors, drives oncogenesis. We focus on the cell cycle-regulated transcription factor LSF, recently shown to be an oncogene for liver cancer. Studies range from critical genes targeted by LSF to control cell cycle progression, to signal transduction pathways that modify LSF to alter its activity, to biological consequences of inhibiting or inducing LSF activity. We also use bioinformatics tools to understand the transcriptional regulatory networks driving proliferation. LSF controls several stages of cell cycle progression. Although its protein levels stay constant in normal cells, its activity is tightly regulated during cell growth stimulation and cell cycle progression. In particular, we have shown that during the critical transition through G1 phase to DNA replication, LSF activity is regulated by phosphorylation at a number of sites, in response to multiple signaling pathways. In this process, the phosphorylation-dependent prolyl isomerase Pin1 binds LSF and alters its activity. At the G1/S transition, LSF contributes to the activation of a number of genes required for DNA replication. Inhibition of LSF causes apoptosis. Under some circumstances, this occurs through inhibition of thymidylate synthase, an essential enzyme for nucleotide biosynthesis and DNA replication that many cancer chemotherapeutic drugs specifically inhibit. A highly specific small molecule inhibitor of LSF activity, which we recently identified, is antiproliferative in many cell types, and drives apoptosis of highly aggressive hepatocellular carcinoma cells. In mouse tumor models, these inhibitors dramatically reduce tumor growth, with no to minimal toxicity to other tissues. Our current interests include developing this, and other LSF small molecule inhibitors, for chemotherapeutics of cancers overexpressing LSF, as is the case for primary liver cancer.