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Thompson S.L.,Norris Cotton Cancer Center | Compton D.A.,Norris Cotton Cancer Center
Journal of Cell Biology | Year: 2010

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation of nondiploid cells such that CIN generates cells with aneuploid genomes that resemble many human tumors. Thus, the p53 pathway plays an important role in limiting the propagation of aneuploid human cells in culture to preserve the diploid karyotype of the population. These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy. © 2010 Thompson and Compton.

Compton D.A.,Norris Cotton Cancer Center
Current Opinion in Cell Biology | Year: 2011

Accurate chromosome segregation during cell division is essential for genome integrity. Errors in chromosome segregation are irreversible and lead to a state of aneuploidy where the number of chromosomes in a cell or organism is not a multiple of the haploid number of chromosomes. Aneuploidy reduces fecundity and is a frequent cause of inherited birth defects. In addition, aneuploidy is very common in solid tumors where it is associated with poor patient prognosis. Recent work has revealed the most common pathways by which chromosomes mis-segregate leading to aneuploidy. Moreover, answers to the key question of how cells respond to aneuploidy are beginning to emerge. © 2010 Elsevier Ltd.

Ceeraz S.,Norris Cotton Cancer Center | Nowak E.C.,Norris Cotton Cancer Center | Noelle R.J.,Norris Cotton Cancer Center | Noelle R.J.,King's College London
Trends in Immunology | Year: 2013

Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target. © 2013 Elsevier Ltd.

Kaur M.,Dartmouth College | Cole M.D.,Norris Cotton Cancer Center
Cancer Research | Year: 2013

The control of normal cell growth is a balance between stimulatory and inhibitory signals. MYC is a pleiotropic transcription factor that both activates and represses a broad range of target genes and is indispensable for cell growth. Whereas much is known about gene activation by MYC, there is no established mechanism for the majority of MYC-repressed genes. We report that MYC transcriptionally activates the PTEN tumor suppressor in normal cells to inactivate the phosphoinositide 3-kinase (PI3K) pathway, thus suppressing AKT activation. Suppression of AKT enhances the activity of the EZH2 histone methyltransferase, a subunit of the epigenetic repressor Polycomb Repressive Complex 2 (PRC2), while simultaneously stabilizing the protein. MYC-mediated enhancement in EZH2 protein level and activity results in local and genome-wide elevation in the repressive H3K27me3 histone modification, leading to widespread gene repression including feedback autoregulation of the MYC gene itself. Depletion of either PTEN or EZH2 and inhibition of the PI3K/AKT pathway leads to gene derepression. Importantly, expression of a phospho-defective EZH2 mutant is sufficient to recapitulate nearly half of all MYC-mediated gene repression. We present a novel epigenetic model for MYC-mediated gene repression and propose that PTEN and MYC exist in homeostatic balance to control normal growth, which is disrupted in cancer cells. © 2012 AACR.

Kisselev A.F.,Norris Cotton Cancer Center | Groettrup M.,University of Konstanz
Current Opinion in Chemical Biology | Year: 2014

Specialized variants of the constitutive 20S proteasome in the immune system like the immunoproteasomes and the thymoproteasome contain active site-bearing subunits which differ in their cleavage priorities and substrate binding pockets. The immunoproteasome plays a crucial role in antigen processing and for the differentiation of pro-inflammatory T helper cells which are involved in the pathogenesis of autoimmunity. Selective inhibitors of the immunoproteasome and constitutive proteasome have recently been generated which interfere with the development and progression of autoimmune diseases. Here we describe these inhibitors and their therapeutic potential as predicted from preclinical models. © 2014 Elsevier Ltd.

Kisselev A.F.,Norris Cotton Cancer Center | Van Der Linden W.A.,Leiden University | Overkleeft H.S.,Leiden University
Chemistry and Biology | Year: 2012

Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade. © 2012 Elsevier Ltd All rights reserved.

Kettenbach A.N.,Norris Cotton Cancer Center | Rush J.,Cell Signaling Technology Inc. | Gerber S.A.,Norris Cotton Cancer Center
Nature Protocols | Year: 2011

In the analysis of biological systems, it is of interest to identify the components of the system and to monitor their changes in abundance under different conditions. The AQUA (for 'absolute quantification') method allows sensitive and specific targeted quantification of protein and post-translational modifications in complex protein mixtures using stable isotopeg-labeled peptides as internal standards. Each AQUA experiment is composed of two stages: method development and application to a biological scenario. In the method development stage, peptides from the protein of interest are chosen and then synthesized with stable isotopes such as 13C, 2H or 15N. The abundance of these internal standards and their endogenous counterparts can be measured by mass spectrometry with selected reaction monitoring or selected ion monitoring methods. Once an AQUA method is established, it can be rapidly applied to a wide range of biological samples, from tissue culture cells to human plasma and tissue. After AQUA peptide synthesis, the development, optimization and application of AQUA analyses to a specific biological problem can be achieved in ∼1 week. Here we demonstrate the usefulness of this method by monitoring both Polo-like kinase 1 (Plk1) protein abundance in multiple lung cancer cell lines and the extent of Plk1 activation loop phosphorylation (pThr-210) during release from S phase. © 2011 Nature America, Inc. All rights reserved.

Rolland S.G.,Norris Cotton Cancer Center | Conradt B.,Norris Cotton Cancer Center
Current Opinion in Cell Biology | Year: 2010

Mitochondria are highly dynamic organelles that constantly fuse and divide. Dynamin-related GTPases are the core components of the machineries that mediate mitochondrial fusion and fission. The role and regulation of these machineries are currently under intense investigation. Recently, members of the BCL2 family of proteins, conserved regulators of apoptosis, have been implicated in the regulation of mitochondrial dynamics. Here, we review the functions of mitochondrial fusion and fission in apoptotic and nonapoptotic cells and how members of the BCL2 family of proteins regulate these functions. © 2010 Elsevier Ltd.

Miller T.W.,Norris Cotton Cancer Center
Clinical Cancer Research | Year: 2014

Low estrogen receptor (ER) levels in breast tumors are associated with poorer response to antiestrogen therapy. Finn and colleagues identify low ER levels as a biomarker predicting benefit from the addition of the EGFR/HER2 dual inhibitor lapatinib to an antiestrogen treatment regimen in patients with metastatic ER+/HER2- breast cancer. © 2014 American Association for Cancer Research.

Sempere L.F.,Norris Cotton Cancer Center
Expert Review of Molecular Diagnostics | Year: 2011

The promise of personalized medicine is highly dependent on the identification of biomarkers that inform diagnostic decisions and treatment options, as well as on the accurate, rapid and cost-effective detection and interpretation of these biomarkers. miRNAs, which are short noncoding regulatory RNAs, are rapidly emerging as a novel class of biomarkers with a unique set of biological and chemical properties that makes them very appealing candidates for theranostic applications in cancer. Since the utility of some protein-encoding gene biomarkers is already exploited in routine clinical practice, it will be important to identify areas in which miRNAs provide complementary or superior information to these existing (and other translational) biomarkers to enhance the diagnostic, prognostic and predictive power of molecular characterization of tumors. In this article, the challenges and opportunities for integration of miRNA-based assays in the clinical toolkit to improve care and management of patients afflicted with solid tumors will be discussed. © 2011 Lorenzo F Sempere.

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