Nicholas Dyson

Department of Medicine
Massachusetts General Hospital Cancer Center
Laboratory of Molecular Oncology
7th floor, Building 149, 13th Street
Charlestown, MA 02129
Tel: (617) 724-9888
Fax: (617) 726-7808
E-mail: dyson@helix.mgh.harvard.edu
6 postdoctoral fellows

Unregulated cell proliferation can kill you.  My laboratory studies the mechanisms that limit cell proliferation in normal cells, and the ways that these controls are eroded in Cancer cells. 

Our research focuses on the E2F transcription factor and the retinoblastoma tumor suppressor (RB). E2F controls the expression of a large number of target genes that are needed for cell proliferation.  This transcriptional program is activated when normal cells are instructed to divide but it is deregulated in tumor cells, where it provides a cellular environment that is permissive for uncontrolled proliferation.  pRB has multiple functions, but one of its most important roles is to limit the activity of E2F; as a result, most tumor cells select for changes that remove this control.

Our current goals are threefold.  First we want to obtain a comprehensive picture of the pathways and genes that impact E2F activity, and that affect E2F regulation by pRB.  We have taken advantage of the fact that Drosophila has a streamlined version of the mammalian RB/E2F families of proteins.  We have used this simplified system to define the roles of individual components, and to carry out genetic screens for interacting pathways that are important in vivo.  Second we want to understand, in molecular detail, how RB/E2F co-ordinates the regulation of its many different targets.  pRB physically interacts with multiple proteins.  We are profiling these interactions and testing the idea that RB-family members link the local regulation of promoter regions with a more general organization of chromosome structure.  Third, using screening approaches, we are learning how to selectively kill cells that have lack RB function and have deregulated E2F activity.

References:

• Moon NS, Di Stefano L, Dyson N (2006) A gradient of EGFR signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis. Mol. Cell. Biol., 26(20):7601-15.
• Longworth MS, Herr A, Ji JY, Dyson NJ (2008) RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes and Development 22(8):1011-24.
• van den Heuvel S, Dyson N (2008) Conserved functions of the Rb and E2F families.  Nature Reviews Molecular Cell Biology, in press.
• Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS, Kwon EJ, Haigis KM, Näär AM, Dyson NJ (2008) E2F1 represses b-catenin transcription and is antagonized by both pRB and CDK8.  Nature, in press.