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Nicholas J. Dyson, PhD

Professor, Department of Medicine, Harvard Medical School

Member, MGH Cancer Center, Massachusetts General Hospital

Contact Info

Nicholas Dyson
Massachusetts General Hospital
Building 149

Charlestown, MA, 02129
Mailstop: Room 7330
Phone: 617-724-9888
Fax: 617-726-7808
dyson@helix.mgh.harvard.edu

Assistant

Not Available.

DF/HCC Program Affiliation

Cancer Genetics
Cancer Cell Biology

Research Abstract

We study the functions of the E2F transcription factor and retinoblastoma (RB) family of proteins, two groups of proteins that are important regulators of cell proliferation. During G1 to S phase progression, the activation of cyclin dependent kinases in G1 leads to the phosphorylation of RB-family proteins (pRB, p107 and p130), and the activation of the E2F-dependent transcription. E2F co-ordinates the expression of a set of genes that encode proteins that are essential for DNA synthesis. This series of events is tightly controlled in normal cells but is deregulated in most, if not all, tumor cells. Viral oncoproteins such as Adenovirus E1A, SV40 large T antigen and E7 proteins of human papillomaviruses have evolved to target RB-family proteins and the viruses exploit these interactions to drive quiescent cells into the cell cycle.

We use a combination of genetic and biochemical approaches to study E2F and RB-family proteins. A major goal is to identify the individual functions of RB-family proteins in the regulation of E2F activity. Because the overexpression of closely related family members often leads to a loss of specificity, our recent efforts have concentrated on loss-of-function approaches. Using primary cells from knockout mice that lack various family members, we have identified E2F-target genes that require either pRB or p107/p130 for their normal patterns of expression and have begun to identify elements of cell cycle control that depend on either pRB, p107 or p130.

To investigate the pathways that converge on E2F and the RB-family we have identified and characterized homologs of E2F (dE2F, dDP) and the RB-family (RBF) in Drosophila. We found that the Drosophila proteins control cell proliferation in ways that are directly analogous to their mammalian counterparts. We have two major goals that exploit the advantages of Drosophila. First, in order to identify the pathways that interact with E2F and RBF, we have set up genetic screens for mutations that modify dE2F/dDP- and RBF-dependent phenotypes. These phenotypes have been generated in transgenic lines by elevating the expression of dE2F, dDP and RBF specifically in the eye. Second, we are characterizing the phenotypes of mutant alleles of dE2F and RBF. Not surprisingly, these mutants have phenotypes that are far more severe than mutations of individual E2F or RB-family members in mice, and are likely to give insight into the general roles of these groups of proteins.

Publications

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