A5059964738- Epigenetics and DNA Methylation
- Hedgehog Signaling Pathway Studies
- Developmental Biology and Gene Regulation
- Cancer-related gene regulation
- Cancer-related Molecular Pathways
- Pluripotent Stem Cells Research
- RNA modifications and cancer
- MicroRNA in disease regulation
- Arsenic contamination and mitigation
- Cancer Cells and Metastasis
- RNA Research and Splicing
- melanin and skin pigmentation
- Histone Deacetylase Inhibitors Research
- Cancer-related molecular mechanisms research
- Ubiquitin and proteasome pathways
- Genomics and Chromatin Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Microtubule and mitosis dynamics
- Pancreatic and Hepatic Oncology Research
- T-cell and Retrovirus Studies
- Birth, Development, and Health
- Animal Genetics and Reproduction
- Mechanisms of cancer metastasis
- Wnt/β-catenin signaling in development and cancer
- Cell death mechanisms and regulation
General Motors (Poland)
2024
University of Miami
2014-2023
Sylvester Comprehensive Cancer Center
2013-2023
Molecular Oncology (United States)
2013-2023
The Wistar Institute
2006-2023
University of Cincinnati
2002-2021
University of Naples Federico II
2017
Dartmouth College
2011-2015
University of Alabama at Birmingham
2015
Cornell University
2015
Notch genes encode a family of transmembrane proteins that are involved in many cellular processes such as differentiation, proliferation, and apoptosis. Although it is well established all four can act oncogenes, the mechanism by which transform cells remains unknown. Previously, we have shown transformation RKE be conditionally induced hormone activation Notchic-estrogen receptor (ER) chimeras. Using this inducible system, show Notchicactivates transcription cyclin D1 gene with rapid...
AbstractRecent work with mouse models and human leukemic samples has shown that gain-of-function mutation(s) in Notch1 is a common genetic event T-cell acute lymphoblastic leukemia (T-ALL). The receptor signals through γ-secretase-dependent process releases intracellular from the membrane to nucleus, where it forms part of transcriptional activator complex. To identify target genes leukemia, we developed lines express doxycycline-dependent manner. Using gene expression profiling chromatin...
The Notch genes of Drosophila melanogaster and vertebrates encode transmembrane receptors that help determine cell fate during development. Although ligands for proteins have been identified, the signaling cascade downstream remains poorly understood. In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages NOTCH1 gene. damage apparently gives rise to constitutively activated version NOTCH protein. Here we show truncated protein resembling found in leukemic cells can...
Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due loss-of-function mutations in BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for targeted null mutation Blm, murine homolog BLM, develop lymphoma earlier than wild-type littermates response challenge leukemia virus and twice number intestinal tumors when crossed carrying Apc tumor suppressor. These observations indicate Blm is modifier formation mouse...
Direct communication between arteries and veins without intervening capillary beds is the primary pathology of arteriovenous malformations (AVMs). Although Notch signaling implicated in embryonic (AV) differentiation, its function adult mammalian vasculature has not been established due to lethality that often occurs both gain- loss-of-function mutants. We expressed a constitutively active Notch4 , int3 mouse endothelium by using tetracycline-repressible system suppress during embryogenesis....
Abstract Given the prevalence of Ras mutations in human cancer, it is critical to understand effector pathways downstream oncogenic leading transformation. To directly assess requirement for Rac1 K-ras–induced tumorigenesis, we employed a model lung cancer which an allele K-ras could be activated by Cre-mediated recombination presence or absence conditional deletion Rac1. We show that function required tumorigenesis this model. Furthermore, although alone was compatible with cell viability...
Abstract K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation murine models sufficient to recapitulate spectrum of lesions seen human ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated a subset PDACs, leading hypothesis Notch1 functions as an this setting. To determine whether required for K-ras–induced tumorigenesis, we used mouse model which oncogenic allele activated deleted simultaneously pancreas....
Abstract The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is putative oncogene non–small cell lung cancer (NSCLC) activation the represents negative prognostic factor. To establish role adenocarcinoma, we directly assessed its requirement Kras-induced tumorigenesis vivo using an autochthonous model adenocarcinoma concomitant expression oncogenic Kras deletion Notch1. We found function required for tumor...
Epigenetic enzymes modulate signal transduction pathways in different biological contexts. We reasoned that epigenetic regulators might the Hedgehog (HH) signaling pathway, a main driver of cell proliferation various cancers including medulloblastoma. To test this hypothesis, we performed an unbiased small-molecule screen utilizing HH-dependent reporter line (Light2 cells). incubated Light2 cells with small molecules targeting modulators and identified four histone deacetylase inhibitors...
Abstract Aberrant Notch signaling contributes to more than half of all human T-cell leukemias, and accumulating evidence indicates involvement in other neoplasms. We developed a tetracycline-inducible mouse model (Top-Notchic) examine the genetic interactions underlying development Notch-induced neoplastic disease. Using this model, we show that suppresses p53 lymphomagenesis through repression ARF-mdm2-p53 tumor surveillance network. Attenuation expression resulted dramatic increase levels...
Notch genes encode a family of transmembrane proteins that are involved in many cellular processes, such as differentiation, proliferation, and apoptosis.It is well established all four can act oncogenes; however, the mechanism by which transform cells remains unknown.Previously, we reported both nuclear localization transcriptional activation required for neoplastic transformation RKE cells.Furthermore, identified cyclin D1 direct target constitutively active molecules.In an effort to...
The c- myc oncogene is among the most commonly overexpressed genes in human cancer. encodes a basic helix–loop–helix/leucine zipper (bHLH/LZ) transcription factor (c-MYC) that activates cascade of downstream targets ultimately mediate cellular transformation. Although large number are regulated by c-MYC, only few have been functionally linked to c-MYC-mediated By expression profiling, metastasis-associated protein 1 (MTA1) gene was identified here as target c-MYC oncoprotein primary cells,...
The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence activating mutations N-Ras and B-Raf, yet clinical development inhibitors this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch an interesting candidate only correlated with progression; a thorough assessment tumor-initiating effects activated on human melanocytes would clarify mounting correlative evidence perhaps identify...
Esophageal adenocarcinoma ranks sixth in cancer mortality the world and its incidence has risen dramatically Western population over last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal underlies resistance to chemotherapy. We present evidence drives a stem cell phenotype by regulating genes establish stemness. Using patient-derived xenograft models, we demonstrate inhibition of gamma-secretase inhibitors (GSI) efficacious downsizing tumor...
The Hedgehog (HH) signaling pathway represents an important class of emerging developmental pathways that play critical roles in the genesis a large number human cancers. pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), key effector HH regulates levels and activity Gli family transcription factors. Although one these compounds, vismodegib, now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations Smo can result...
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how suppresses formation of is still obscure. Deletion p18(Ink4c) (p18), an inhibitor CDK4 CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, leads spontaneous tumor development. Alternately, germline Brca1 shifts fate cells cause luminal-to-basal transformation. Here, we report that disrupting by either or...
Abstract In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of neoplastic phenotype cancer stem cells, which may allude its additional involvement metastasis resistance therapy. Therefore, is an exceedingly attractive therapeutic target cancer, but full range potential targets within pathway underexplored. To date, there are no small-molecule inhibitors that directly intracellular or assembly transcriptional activation complex....
Notch proteins are plasma membrane-spanning receptors that mediate important cell fate decisions such as differentiation, proliferation, and apoptosis. The mechanism of signaling remains poorly understood. However, it is clear the pathway mediates its effects through intercellular contact between neighboring cells. prevailing model for suggests ligand, presented on a cell, triggers proteolytic processing Notch. Following proteolysis, thought intracellular portion (Nic) translocates to...
JAGGED1 is a member of the Delta/Serrate/Lag-2 (DSL) family proteins that are cell-bound ligands for Notch receptors. Initiation signaling occurs through series proteolytic events upon binding to DSL protein presented on neighboring cells. Whether themselves capable initiating an intrinsic mechanism within cell they expressed not known. Aberrant misexpression and DELTA1 has been documented in several human tumors; however, by which contributes oncogenesis elucidated. We report expression...
The Rel family of proteins includes a number involved in transcriptional control, such as the retroviral oncoprotein v-Rel, c-Rel, Drosophila melanogaster developmental protein Dorsal, and subunits transcription factor NF-kappa B. These are related through highly conserved domain approximately 300 amino acids, called homology domain, that contains dimerization, DNA binding, nuclear targeting functions. Also within there is consensus sequence (Arg-Arg-Pro-Ser) for phosphorylation by cyclic...