A5039143074- RNA modifications and cancer
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- Histone Deacetylase Inhibitors Research
- Ferroptosis and cancer prognosis
- Wnt/β-catenin signaling in development and cancer
- Cancer, Hypoxia, and Metabolism
- Multiple Myeloma Research and Treatments
- Developmental Biology and Gene Regulation
- Cancer-related Molecular Pathways
- ATP Synthase and ATPases Research
- Cancer-related molecular mechanisms research
- Ubiquitin and proteasome pathways
- Zebrafish Biomedical Research Applications
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Lipid metabolism and disorders
- Glutathione Transferases and Polymorphisms
- Digestive system and related health
- Receptor Mechanisms and Signaling
- Hedgehog Signaling Pathway Studies
- Genetics and Neurodevelopmental Disorders
- Amino Acid Enzymes and Metabolism
- Sphingolipid Metabolism and Signaling
Michigan State University
2024-2025
Henry Ford Health System
2025
University of Maryland, Baltimore
2019-2023
Vanderbilt University
2016-2023
University of Maryland Medical Center
2023
Vanderbilt University Medical Center
2014-2018
Pediatrics and Genetics
2015
Kabuki syndrome (KS) is a rare multiple congenital anomaly characterized by distinctive facial features, global developmental delay, intellectual disability and cardiovascular musculoskeletal abnormalities. While mutations in KMT2D have been identified majority of KS patients, few patients KDM6A. We analyzed 40 individuals clinically diagnosed with for Mutations were detected 12 KDM6A 4 cases, respectively. Observed included single-nucleotide variations indels leading to frame shifts,...
Abstract Background Glioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades research, the survival rates for GBM remain effectively stagnant. A defining hallmark is highly acidic tumor microenvironment, which thought to activate pro-tumorigenic pathways. This acidification result altered metabolism favoring aerobic glycolysis, phenomenon known Warburg effect. Low extracellular pH...
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....
Purpose: The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression oncogenic transcription factors, including MYC. However, the preclinical advanced solid moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to colorectal cancer.Experimental Design: Using panel molecularly...
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted systematic forward genetic analysis through reporter-based screens haploid human cells. Comparison for negative, attenuating and positive regulators mediators R-spondin-dependent suppressors...
Abstract Disruption of extracellular pH and proton‐sensing can profoundly impact cellular protein functions, leading to developmental defects. To visualize changes in the developing embryo, we generated a zebrafish transgenic line that ubiquitously expresses ratiometric pH‐sensitive fluorescent pHluorin2, tethered face plasma membrane using glycosylphosphatidylinositol (GPI) anchor. Monitoring pHluorin2 with fluorescence revealed dynamic discrete domains acidification over first 72 h...
Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), small molecule inhibitor GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 key pro-survival pathway in glioblastoma cells. Here, demonstrate inhibition also induces ferroptosis lung cell carcinoma (A549) and pancreatic ductal adenocarcinoma (Panc02) Moreover, OGM synergized with ionizing radiation induce lipid...
Abstract Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding IMiDs to Cereblon (CRBN), substrate receptor CRL4 CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates degradation. Despite this clinical significance, physiological regulation remains largely unknown. Herein we demonstrate that Wnt, extracellular ligand an essential signal transduction pathway, promotes CRBN-dependent degradation a...
Abstract The relative abundance of Wnt receptors plays a crucial role in controlling signaling tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate are well-characterized, deubiquitylase reverses these reactions remains unclear. Herein, we identify USP46, UAF1, WDR20 (USP46 complex) as positive regulators cultured cells. We find USP46 complex is similarly required for Xenopus zebrafish embryos. demonstrate promotes association between cell surface coreceptor,...
A small-molecule CK1α activator inhibits the growth of WNT-driven intestinal tumors without toxicity to normal epithelium.
During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at centriole to nuclear envelope. This developmentally programmed process, referred centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences biology, and whether disruption results human cardiac disease,...
ABSTRACT X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate signaling pathways, including Wnt signaling. regulates by promoting the monoubiquitylation co-repressor Groucho/TLE family proteins, decreasing its affinity for TCF/Lef transcription factors and allowing assembly transcriptionally active β-catenin–TCF/Lef complexes. We now demonstrate that is phosphorylated GSK3 at threonine 180, alanine mutant...
Inhibition and knockdown of GPR68 negatively affects glioblastoma cell survival in vitro by inducing ferroptosis. Herein, we aimed to demonstrate that inhibition reduces the cells vivo using two orthotopic larval xenograft models Danio rerio, GBM lines U87-MG U138-MG. In cancer was assessed setting or knockdown. vitro, shRNA-mediated demonstrated potent cytotoxic effects against U87 U138 lines. This effect associated with increased intracellular lipid peroxidation, suggesting ferroptosis as...
The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that coordinates progression through the cell cycle by temporally and spatially promoting degradation of key proteins. Many these targeted proteins have been shown to play important roles in regulating orderly cycle. Using previously described Drosophila vitro expression cloning approach, we screened for new substrates APC Xenopus egg extract identified MCPH1 (dMCPH1), protein encoded homolog causative gene autosomal...
Abstract Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute hepatic fibrosis, but role BMP development NAFLD unclear. In this study, treatment with either two inhibitors reduced triglyceride content diabetic ( db/db ) mice. inhibitor-induced decrease levels was associated decreased mRNA encoding Dgat2, an enzyme integral synthesis. Treatment hepatoma cells BMP2 induced DGAT2 expression...
Upon Notch pathway activation, the receptor is cleaved to release intracellular domain (NICD), which translocates nucleus activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in N1-Box inhibit NICD1 degradation and transferable for promotion of heterologous proteins extracts cultured human cells. Mutation enhances Notch1 activity cells zebrafish embryos. Human cancer within enhance signaling...
Cdc14 is an evolutionarily conserved serine/threoninephosphatase. Originally identified in S. cerevisiae as a cell cycle regulator, its role other eukaryotic organisms remains unclear. In Drosophila melanogaster, encoded by single gene, thus facilitating study. We found that expression highest the testis of adult flies and cdc14 null are viable. female male do not display altered fertility. males, however, exhibit decreased sperm competitiveness. Previous studies have shown plays...
The Cullin-RING ligase 4 E3 ubiquitin component Cereblon (CRBN) is a well-established target for class of small molecules termed immunomodulatory drugs (IMiDs). These drive CRBN to modulate the degradation number neosubstrates required growth multiple cancers. Whereas mechanism underlying activation by IMiDs well described, normal physiological regulation poorly understood. We recently showed that activated following exposure Wnt ligands and subsequently mediates subset substrates. Among...
A century after Otto Warburg's seminal discovery of aerobic glycolysis in cancer cells, a phenomenon dubbed the "Warburg effect", mechanistic links between this metabolic rewiring and tumorigenesis remain elusive. Warburg postulated that enhanced glucose fermentation to lactate, even presence oxygen, stemmed from an "irreversible respiratory injury" intrinsic cells. While oxidative phosphorylation yields higher ATP, effect paradoxically persists, suggesting excess lactate acid production are...
Abstract An acidic milieu is a hallmark of the glycolytic metabolism that occurs in cancerous cells. The environment known to promote cancer progression, but underlying signaling and cell biological underpinnings these phenomena are not well understood. Here, we describe ogremorphin, first-in-class small-molecule inhibitor GPR68, an extracellular proton-sensing mechanosensing G protein–coupled receptor. Ogremorphin was discovered chemical genetic zebrafish screen for its ability perturb...
Abstract Wnt signaling is at the core of animal development and regeneration. It controls cell proliferation, differentiation survival. In humans, defective leads to several forms cancer, most notably colorectal cancer (CRC). A convergence methodological advances enabled us do a systematic forward genetic analysis canonical in human cells, revealing new players regulatory mechanisms. Using HAP1 haploid line, we conducted set genome-wide screens interrogate pathway under normal pathological...
<div>Abstract<p>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...
<p>Primary screen of CADD-derived compounds.</p>