Research Abstract:
A major focus of our lab is the retinoblastoma (Rb) tumor suppressor pathway, which regulates cell cycle, differentiation, senescence and apoptosis. Rb is directly mutated or functionally inhibited in virtually all human cancer cells. Recently, we have shown using melanoma as a model system that terminal differentiation creates a selective pressure to mutate the Rb pathway to allow cells to re-enter the cell cycle, which may explain the strong tendency for melanomas to acquire mutations affecting the p16Ink4a tumor suppressor. Studies are underway to further understand the role of Rb in tumor suppression in melanoma.
The other major focus of the lab is the relationship between developmental lineage and tumor phenotype. We have identified a malignant switch that occurs during melanoma progression. This malignant switch is associated with regression to a primordial phenotype within the developmental lineage of melanocytes through a distinct mesenchymal to epithelial transition. Studies are underway to identify the molecular mechanisms of this malignant switch.
Selected Publications:
Onken MD, Ehlers JP, Worley LA, et al. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res 2006 66:4602-4609.
Loercher AE, Tank EM, Delston RB, Harbour JW. MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J Cell Biol 2005 168:35-40.
Ma D, Zhou P, Harbour JW. Distinct mechanisms for regulating the tumor suppressor and anti-apoptotic functions of Rb. J Biol Chem 2003 278:19358-19366.
Zhang HS, Gavin M, Dahiya A, et al. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 2000 101:79-89.
Harbour JW, Luo RX, Dei Sante A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999 98:859-869.
Last Updated: 03/12/2007 |