Nicholas Dyson, PhD
Professor of Medicine
Harvard Medical School
James and Shirley Curvey MGH Research Scholar
Mass General Cancer Center
Center for Cancer Research
The Dyson Lab studies the role of the retinoblastoma tumor suppressor gene (RB). In normal cells, RB enables cells to stop dividing. RB is inactivated in many types of cancer, and this change is thought to be an important step in tumor progression. We are studying the ways in which the loss of RB alters the cell. Our goals are to find ways to correct the specific defects that promote tumor development and to find ways to enhance any changes that might be points of weakness that are specific to the tumor cells. In some cancers, tumor cells still express RB, but the protein has too little activity to stop cell division. We are searching for ways to enhance the activity of pRB since, in these types of cancer, they may help RB to stop tumor cell proliferation.
Nicholas Dyson, PhD
Principal InvestigatorGroup Members
We investigate 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, providing 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.
The original discovery of the RB1 gene was made possible by the fact that its mutation is a causal and rate-limiting event in the development of retinoblastoma. An exciting new development in this area of research is the discovery that the loss of pRB undermines genomic stability.
In two recently published studies, we have examined the causes and consequences of pRB inactivation. A careful analysis of pRB-deficient cells has revealed that pRB loss leads to centromere dysfunction, reduced cohesion, and chromosome instability (CIN). CIN is a common feature in tumor cells. High levels of CIN correlate with poor prognosis and promote tumor relapse after seemingly effective anticancer treatments. The finding that pRB loss causes CIN raises the possibility that the functional inactivation of pRB may be an underlying source of much of the aneuploidy seen in tumor cells. Understanding what causes these changes may have therapeutic implications, and a major goal of our current work is to find ways to suppress these defects. Such conditions may limit the ability of pRB-deficient tumor cells to evolve.
In a second set of experiments, we sought to identify pathways that either enhance or suppress the ability of pRB to function. Although pRB is typically viewed as a target of cdk regulation, a screen of the kinome revealed that multiple kinases have a major impact on the capability of pRB to arrest the cell cycle and/or induce senescence. Interestingly, one such kinase was LATS2, a component of the HIPPO pathway. Subsequent experiments revealed that LATS2 is important for the activation of DREAM repressor complexes, and that the ability of pRB to trigger the formation of DREAM complexes was compromised when LATS2 levels were low. LATS2 is closely linked to the RB gene on human chromosome 13, and a large proportion of cancer cells show loss of heterozygosity for RB1 and LATS2, but apparently fail to mutate the remaining allele of RB1. We speculate that heterozygosity for LATS2 may reduce the need to mutate RB1. Potentially, increasing LATS2 activity in these cells may enhance the ability of pRB to block cell proliferation.
Postdoctoral Position (1)
A postdoctoral position is available in the laboratory of Nick Dyson at the Massachusetts General Hospital Cancer Center/Harvard Medical School. Our research is focused on the control of cell proliferation, specifically on the roles of the E2F transcription factor and its regulation by Rb family of proteins. Ongoing projects include genetic screens for modifiers of E2F-dependent apoptosis, E2F-induced apoptosis and studies of chromatin regulation. Deregulated E2F activity drives cell proliferation in a large proportion of Cancers and a major goal of the laboratory is to use Drosophila as a model system to understand the roles of E2F/RB proteins, and then to apply this information to studies of mammalian cells, particularly human cancer cells. Candidates should be highly motivated and have a strong background in Drosophila genetics and/or developmental biology. Applicants must have a PhD or MD or equivalent, and less than four years of post-doctoral experience.
To apply send a cover letter, CV, and three letters of recommendation.
Nick Dyson, PhD
Massachusetts General Hospital Cancer Center
13th Street, Bldg. 149, 7th Floor
Charlestown, MA 02129
Dr. Dyson, a senior scientist at the Center for Cancer Research, has made breakthroughs in our understanding of the way cells divide, whether it is the regulated division of a normal cell or the abnormal proliferation of a malignant cancer.
Nick Dyson, PhD, has been appointed scientific director of the Mass General Cancer Center.
The second group of MGH Research Scholars – recipients of unrestricted five-year grants to support innovative investigations – was announced at the hospital’s Research Advisory Council (RAC) annual meeting on May 11.
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