A5067690876- Microtubule and mitosis dynamics
- Genomics and Chromatin Dynamics
- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- Cellular transport and secretion
- Epigenetics and DNA Methylation
- DNA and Nucleic Acid Chemistry
- Photosynthetic Processes and Mechanisms
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Cellular Mechanics and Interactions
- PARP inhibition in cancer therapy
- Genomic variations and chromosomal abnormalities
- Protist diversity and phylogeny
- Cancer, Hypoxia, and Metabolism
- Pluripotent Stem Cells Research
- Fungal and yeast genetics research
- Chromosomal and Genetic Variations
- Bioinformatics and Genomic Networks
- Acute Myeloid Leukemia Research
- Gene Regulatory Network Analysis
- Hippo pathway signaling and YAP/TAZ
- Cell Image Analysis Techniques
- Lung Cancer Research Studies
- Chronic Myeloid Leukemia Treatments
Worcester Polytechnic Institute
2016-2023
Massachusetts General Hospital
2010-2016
Harvard University
2010-2016
Harvard University Press
2012
State Street (United States)
2011
Dartmouth College
2007-2010
USC Norris Comprehensive Cancer Center
2010
Cotton (United States)
2010
Dartmouth–Hitchcock Medical Center
2009
Brandeis University
2003
Retinoblastoma is an aggressive childhood cancer of the developing retina that initiated by biallelic loss RB1. Tumours progress very quickly following RB1 inactivation but underlying mechanism not known. Here we show retinoblastoma genome stable, multiple pathways can be epigenetically deregulated. To identify mutations cooperate with loss, performed whole-genome sequencing retinoblastomas. The overall mutational rate was low; only known gene mutated. We then evaluated role in stability and...
Formins have conserved roles in cell polarity and cytokinesis directly nucleate actin filament assembly through their FH2 domain. Here, we define the active region of yeast formin Bni1 domain show that it dimerizes. Mutations disrupt dimerization abolish activity, suggesting dimers are state domains. The protects growing barbed ends filaments from vast excesses capping protein, dimer maintains a persistent association during elongation. This is not species-specific mechanism, as activities...
Chromosome instability (CIN) is a common feature of tumor cells. By monitoring chromosome segregation, we show that depletion the retinoblastoma protein (pRB) causes rates missegregation comparable with those seen in CIN The suppressor frequently inactivated human cancers and best known for its regulation G1/S-phase transition. Recent studies have shown pRB inactivation also slows mitotic progression promotes aneuploidy, but reasons these phenotypes are not well understood. Here describe...
The human genome has three unique genes coding for kinesin-13 proteins called Kif2a, Kif2b, and MCAK (Kif2c). Kif2a have documented roles in mitosis, but the function of Kif2b not been defined. Here, we show that is expressed at very low levels cultured cells GFP-Kif2b localizes predominately to centrosomes midbodies, also spindle microtubules transiently kinetochores. Kif2b-deficient assemble monopolar or disorganized spindles. Chromosomes typical kinetochore-microtubule attachments,...
The transition between proliferation and quiescence is frequently associated with changes in gene expression, extent of chromatin compaction, histone modifications, but whether state actually regulate cell cycle exit unclear. We find that primary human fibroblasts induced into exhibit tighter compaction. Mass spectrometry analysis modifications reveals H4K20me2 H4K20me3 increase other are present at similar levels proliferating quiescent cells. Analysis cells S, G 2 /M, 1 phases shows...
The retinoblastoma tumor suppressor (pRb) protein associates with chromatin and regulates gene expression. Numerous studies have identified Rb -dependent RNA signatures, but the proteomic effects of loss are largely unexplored. We acutely ablated in adult mice conducted a quantitative analysis changes colon lungs, where KO was sufficient or insufficient to induce ectopic proliferation, respectively. As expected, caused similar increases classic pRb/E2F-regulated transcripts both tissues,...
The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of is common in tumors, mutations core components are rare. Thus, understanding how tumor cells inactivate signaling remains a key unresolved question. Here, we identify kinase STK25 as an activator signaling. We demonstrate that loss promotes YAP/TAZ activation enhanced cellular proliferation, even under normally growth-suppressive...
Aberrant expression of aurora kinase A is implicated in the genesis various neoplasms, including acute myeloid leukemia. Alisertib, an inhibitor, has demonstrated efficacy as monotherapy trials malignancy, and this appears enhanced combination with conventional chemotherapies. In phase I, dose-escalation study, newly diagnosed patients received induction cytarabine idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive...
The presence of supernumerary centrosomes is prevalent in cancer, where they promote the formation transient multipolar mitotic spindles. Active clustering enables a functional bipolar spindle that competent to complete division. Disruption pole cancer cells promotes division and generation non-proliferative daughter with compromised viability. Hence molecular pathways required for centrosomes, but dispensable normal cells, are promising therapeutic targets. Here we demonstrate Aurora A...
During cell division, the microtubule nucleating and organizing organelle, known as centrosome, is a critical component of mitotic spindle. In cells with two centrosomes, each centrosome functions an anchor point for microtubules, leading to formation bipolar spindle progression through division. When extra centrosomes are present, multipolar spindles form parent may divide into more than daughter cells. Cells that born from divisions not viable, hence clustering division determinants...
The retinoblastoma tumor suppressor protein (RB) interacts physically and functionally with a number of epigenetic modifying enzymes to control transcriptional regulation, respond replication stress, promote DNA damage response repair, regulate genome stability. To better understand how disruption RB function impacts regulation stability determine whether such changes represent exploitable weaknesses RB-deficient cancer cells, we performed an imaging-based screen identify inhibitors that...