Dr. Alain Nepveu will be the keynote speaker for the 2014 Biochemistry Summer Symposium. Dr. Nepveu's talk will be Wednesday August 13th, 2014 from 12:30-1:30pm at the Suncor Fluvarium.
TItle: A Strange Case of Dr. Jekyll and Mr. Hyde: CUX1, a Haploinsufficient Tumour Suppressor Gene Overexpressed in Advanced Cancers
Abstract: Cancer cells exhibit stress phenotypes that select for extensive adaptations in cellular processes that are not themselves oncogenic. The concept of "non-oncogene addiction" depicts the acute dependency of tumour cells on heightened activity of certain genes that are not themselves classical oncogenes. I will describe two cases of non-oncogene addiction involving distinct protein isoforms of the Cut homeobox 1 (CUX1) gene.
The presence of multiple centrosomes in normal cells causes multipolar mitosis and the generation of non-viable daughter cells. Increased p110 CUX1 expression in cancer cells activates a transcriptional program that reinforces the spindle assembly checkpoint and delays mitosis until centrosomes have clustered to enable normal, bipolar mitosis. Yet, the passage through a multipolar intermediate increases the frequency of chromosome missegregation leading to the rapid generation of aneuploid populations from which cells with increased tumourigenic potential emerge.
Cells that harbor an activated RAS oncogene produce an excess of reactive oxygen species (ROS) that cause oxidative DNA damage. In primary cells, this leads to cellular senescence. In cancer cells, this DNA damage stress selects for increased expression of p200 CUX1 which functions as an accessory factor in base excision repair, the pathway that repairs most oxidative DNA lesions. The heightened dependency of RAS-transformed cells on base excision repair provides a therapeutic window that can be exploited with drugs that specifically target this pathway.