Department of Biochemistry
Biological roles and molecular functions of the mammalian CUX1 homeodomain protein
Rosalind and Morris Goodman Cancer Centre
The Cancer Research Building
1160 Pine Avenue
Office: Room 414; Lab: Room 411
Montreal, Quebec H3A 1A3
Tel: 514-398-5839; Lab: 514-398-5163
alain [dot] nepveu [at] mcgill [dot] ca
1984 - PhD, Universite de Sherbrooke
Our laboratory is interested in the regulation of transcription in mammalian cells and, in particular, how gene regulation is disrupted in cancer cells. Using tissue culture models as well as transgenic mouse models, we investigate the consequences of aberrant gene regulation on basic cellular processes like cell cycle progression, cell motility and genetic instability. There are currently 4 main research theme in the laboratory.
In one project, we investigate the regulation and function of the CUX1 transcription factor during cell cycle progression. We study how phosphorylation by several kinases impart 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 into S phase.
Cell populations able to generate large repertoires of genetic variants have increased potential to generate tumor cells that will prevail through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary centrosomes, however, can lead to multipolar mitosis and cell death. In this project, we investigate a transcriptional program that enable cells to mount a robust spindle assembly checkpoint in mitosis. This, in turn, enables the survival of tetraploid cells that evolve to become aneuploid and tumorigenic.
In another project, 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 two sets of transcriptional targets of CUX1 in the context of mammary gland tumors: those that mediate its stimulatory effect on cell motility and invasion and those that are responsible for the autocrine stimulation of the Wnt/Beta-catenin pathway.
In a separate project, we investigate the mechanisms by which point mutations are generated in mammalian cells. In particular, we study how the process of mutagenesis can be regulated in response to various forms of stress including DNA damage. We investigate a pathway whereby DNA damage activates checkpoint kinases which phosphorylate some transcription factors thereby creating binding sites for error-prone DNA polymerases that are then recruited to specific transcription units.
Publications - Alain Nepveu