A5079722548- Pancreatic and Hepatic Oncology Research
- Pancreatitis Pathology and Treatment
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- Metabolism, Diabetes, and Cancer
- Genomics and Chromatin Dynamics
- MicroRNA in disease regulation
- Hematopoietic Stem Cell Transplantation
- Pancreatic function and diabetes
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- Cancer Cells and Metastasis
- Virus-based gene therapy research
- PI3K/AKT/mTOR signaling in cancer
- Genetic Mapping and Diversity in Plants and Animals
- Cytokine Signaling Pathways and Interactions
- Growth Hormone and Insulin-like Growth Factors
- Telomeres, Telomerase, and Senescence
- Protein Kinase Regulation and GTPase Signaling
- Cancer Research and Treatments
- DNA Repair Mechanisms
- Acute Myeloid Leukemia Research
- Bioinformatics and Genomic Networks
- CAR-T cell therapy research
- Arsenic contamination and mitigation
George Washington University
2015-2023
GW Medical Faculty Associates
2017-2018
Harvard University
2008-2013
Massachusetts General Hospital
2008-2013
New York University
2011
European Institute of Oncology
2011
Tufts Medical Center
2007-2009
Molecular Oncology (United States)
2007-2009
Pine Manor College
2008
Tufts University
2008
Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target rapamycin)-mediated phosphorylation insulin receptor substrate 1 (IRS-1). Raptor directly binds serves as a scaffold mTOR-mediated...
The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer survival, and inflammation. In the pancreas, dispensable for normal development, whereas majority pancreatic ductal adenocarcinomas (PDAC) show constitutive activation STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define mechanisms functional importance PDAC pathogenesis. Large-scale screening lines with JAK2 inhibitor that blocks function revealed more than...
Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis pancreatic ductal adenocarcinoma (PDAC), one most lethal human cancers. found that KDM2B (also known as Ndy1, FBXL10, JHDM1B), an H3K36 histone demethylase implicated bypass cellular senescence somatic reprogramming, is markedly overexpressed PDAC, with levels increasing disease grade stage, highest expression metastases. silencing...
The histone H3 demethylase Not dead yet-1 (Ndy1/KDM2B) is a physiological inhibitor of senescence. Here, we show that Ndy1 down-regulated during senescence in mouse embryonic fibroblasts (MEFs) and it represses the Ink4a/Arf locus. counteracts senescence-associated down-regulation Ezh2, component polycomb-repressive complex (PRC) 2, via JmjC domain-dependent process leading to global locus-specific up-regulation H3K27 trimethylation. latter promotes binding Bmi1, PRC1. Ndy1, which interacts...
Energy depletion activates AMP-activated protein kinase (AMPK) and inhibits cell growth via TSC2-dependent suppression of mTORC1 signaling. Long term energy also induces apoptosis by mechanisms that are not well understood to date. Here we show AMPK, activated depletion, inhibited survival binding phosphorylating IRS-1 at Ser-794. Phosphorylation this site phosphatidylinositol 3-kinase/Akt signaling, suppressed the mitochondrial membrane potential, promoted apoptosis. Of treatments promoting...
A common integration site, cloned from MoMuLV-induced rat T cell lymphomas, was mapped immediately upstream of Not dead yet-1 ( Ndy1 )/ KDM2B , a gene expressed primarily in testis, spleen, and thymus, that is also known as FBXL10 or JHDM1B. encodes nuclear, chromatin-associated protein harbors Jumonji C (JmjC), CXXC, PHD, proline-rich, F-box, leucine-rich repeat domains. its homolog Ndy2/KDM2A FBXL11 JHDM1A ), which target provirus retrovirus-induced encode proteins were recently shown to...
Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that is a conserved regulator lifespan multiple cell types and defines program which this chromatin-modifying enzyme counteracts senescence-associated down-regulation EZH2 methyltransferase. Senescence MEFs epigenetically silences induces tumor suppressor miRNAs <i>let-7b</i> <i>miR-101</i>, target EZH2. Forced promotes...
The development of the hematopoietic system is a dynamic process that controlled by interplay between transcriptional and epigenetic networks to determine cellular identity. These are critical for lineage specification frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as regulator definitive hematopoiesis commitment murine stem progenitor cells (HSPCs). RNA sequencing Kdm2b-null HSPCs genome-wide ChIP studies human leukemias revealed cooperates with polycomb...
Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential urgently needed. In this study, we aimed identify novel genes that drive metastasis BLBC elucidate underlying mechanisms action.An unbiased approach using gene expression profiling a progression model in silico leveraging pre-existing tumor transcriptomes...
Leptin biosynthesis in adipose cells vivo is increased by food intake and decreased deprivation. However, the mechanism that couples leptin production to remains unknown. We found addition of leucine isolated rat adipocytes significantly these cells, suggesting postprandial levels may be directly regulated dietary leucine. The effect was inhibited rapamycin not actinomycin D. Besides, administration did increase amount mRNA adipocytes. Therefore, we concluded activates expression at level...
The CCCTC-binding zinc-finger protein (CTCF)-mediated network of long-range chromatin interactions is important for genome organization and function. Although this has been considered largely invariant, we find that it exhibits extensive cell-type-specific contribute to cell identity. Here, present Lollipop, a machine-learning framework, which predicts CTCF-mediated using genomic epigenomic features. Using ChIA-PET data as benchmark, demonstrate Lollipop accurately both within across types,...
Abstract Disruption of the TGF-β pathway is associated with liver fibrosis and suppression tumorigenesis, conditions low Vitamin D (VD) levels. However, potential contributions VD to tumor progression in context signaling remain unexplored. Our analyses deprivation (VDD) vivo models formation revealed striking three-fold increases burden Smad3 +/− mice, a increase TLR7 expression compared controls. ChIP transcriptional assays confirm binding at two promoter SBE sites. Molecular interactions...
Exposure to genotoxins such as ethanol‐derived acetaldehyde leads DNA damage and liver injury promotes the development of cancer. We report here a major role for transforming growth factor β/mothers against decapentaplegic homolog 3 adaptor β2‐Spectrin (β2SP, gene Sptbn1 ) in maintaining genomic stability following alcohol‐induced damage. β2SP supports repair through β2SP‐dependent activation Fanconi anemia complementation group D2 (Fancd2), core component complex. Loss decreased Fancd2...
Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression normal lungs identify candidates associated with lung cancer. Indeed, most of the lung-enriched identified our analysis have known or suspected roles focused on encoding neuron-derived neurotrophic factor (NDNF), which had not yet been determined NDNF...
Abstract Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with history chronic and occurs in 25% ductal adenocarcinomas 40% acinar cell carcinomas. Deletion or Bap1 murine pancreata causes genomic instability, tissue damage, full penetrance. Concomitant expression Kras G12D leads to predominantly intraductal papillary mucinous neoplasms...
Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of stem/progenitor (HSPC) compartment. To retain HSC activity, KIT, a receptor tyrosine kinase, in HSCs activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing differentiation....