Dr. Nepveu’s laboratory is interested in the regulation of transcription in mammalian cells and, in particular, how it relates to the initiation and progression of cancer. There are currently four main research themes in the laboratory:
1) The regulation and function of the CUX1 transcription factor during cell cycle progression - We study how phosphorylation by several kinases impact on CUX1 activity in different phases of the cell cycle. In turn, we analyze how transcriptional activation and repression of specific sets of genes by CUX1 can accelerate the start of DNA replication and stimulate the progression from the G1 phase to S phase.
2) CUX1 was shown to up-regulate the expression of several genes that play important roles in mitosis and the spindle assembly checkpoint. While this activity ensures proper chromosomal segregation in normal cells, higher CUX1 expression in cancer cells can lead to chromosomal instability following cytokinesis failure. Using tissue culture models and transgenic mice, we investigate how chromosomal instability enables tumor cells to evolve and acquire novel metastatic properties.
3) We use transgenic mouse models to investigate how elevated CUX1 expression, as observed in human cancers, can contribute to the development of primary tumors in the mammary gland and their progression to the metastatic state. We investigate the role of CUX1 in the autocrine activation of the Wnt/beta-catenin pathway, and we study the interactions between tumor cells and stromal cells that promote invasion and metastasis.
4) In a separate project, we investigate the mechanisms by which point mutations are generated in mammalian cells. Recent evidence indicates that mutagenesis is not an entirely random process but is controlled, to some extent, in time and space. Indeed, the frequency of mutations can be modulated by regulatory sequences and physiological contexts.