A5103012067- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Renal cell carcinoma treatment
- Cancer Research and Treatment
- Mathematical Biology Tumor Growth
- Cancer-related gene regulation
- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- Pancreatic and Hepatic Oncology Research
- Prenatal Screening and Diagnostics
- Cell Adhesion Molecules Research
- Hemoglobinopathies and Related Disorders
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Lymphoma Diagnosis and Treatment
- Lung Cancer Research Studies
- Chromatin Remodeling and Cancer
- Protein Tyrosine Phosphatases
- Histone Deacetylase Inhibitors Research
- Genetics and Physical Performance
- Receptor Mechanisms and Signaling
- Renal and related cancers
- Neuroendocrine Tumor Research Advances
- Genomics and Rare Diseases
- Caveolin-1 and cellular processes
Cleveland Clinic
2008-2023
University of Chicago
2010
Case Western Reserve University
1996-2009
Cleveland Clinic Lerner College of Medicine
2007
Institute of Molecular and Cell Biology
1998-2003
Megmilk Snow Brand (Japan)
1996
Background Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal (HbF) interferes with this polymerization, but HbF epigenetically silenced from infancy onward DNA methyltransferase 1 (DNMT1). Methods findings To pharmacologically re-induce DNMT1 inhibition, first-in-human clinical trial (NCT01685515) combined 2 small molecules—decitabine to...
We investigated the molecular and cellular actions of receptor protein tyrosine phosphatase (PTP) α in integrin signaling using immortalized fibroblasts derived from wild-type PTPα-deficient mouse embryos. Defects PTPα−/− migration a wound healing assay were associated with altered cell shape focal adhesion kinase (FAK) phosphorylation. The reduced haptotaxis to fibronectin (FN) cells was increased by expression active (but not inactive) PTPα. Integrin-mediated formation src–FAK fyn–FAK...
Abstract Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve interaction with ezrin, established mediator metastasis. Here, we show overexpression MCF7 PC3 cell lines increased their vitro invasive migratory potential led to expression matrix metalloproteases 1 9 (MMP1 MMP9)....
We document for the first time that sanctuary in an organ which expresses high levels of enzyme cytidine deaminase (CDA) is a mechanism cancer cell resistance to analogues. This could explain why historically, analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy vitro. Importantly, this can be readily reversed, without increasing toxicity sensitive organs, by combining analogue with inhibitor (tetrahydrouridine). Specifically, CDA rapidly...
The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm chromosome 8 (8p). Genes on remaining homologous chromosome, however, are not recurrently mutated, and identity key 8p tumor-suppressor genes (TSG) unknown. In this work, analysis minimal commonly deleted segments to identify candidate TSG implicated GATA4, a master transcription factor driver hepatocyte epithelial lineage fate. murine model, liver-conditional deletion 1 Gata4 allele model...
Abstract The cytosine analogue decitabine alters hematopoietic differentiation. For example, treatment increases self-renewal of normal stem cells. mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability deplete chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role transcription repression. HOXB4 is factor that promotes cell self-renewal. In precursors induced differentiate by...
Abstract Nuclear factor kappa B (NFκB) is a central participant in the metastasis and chemoresistance of colorectal cancer (CRC). However, it not fully understood to what extent NFκB contributes induction metastasis‐associated matrix metalloprotease‐9 ( MMP‐9 ) gene sensitivity commonly used chemotherapeutic 5‐fluorouracil (5‐Fu) CRC. Using RKO human CRC cell line two signaling deficient mutants, we investigated NFκB's role 5‐Fu cells. plays predominant cells, as evidenced by failure tumor...
Abstract Current drug therapy for metastatic renal cell cancer (RCC) results in temporary disease control but not cure, necessitating continued investigation into alternative mechanistic approaches. Drugs that inhibit chromatin-modifying enzymes involved transcription repression (chromatin-relaxing drugs) could have a role, by inducing apoptosis and/or through differentiation pathways. At low doses, the cytosine analogue decitabine (DAC) can be used to deplete DNA methyl-transferase 1...
The two tandem homologous catalytic domains of PTPα possess different kinetic properties, with the membrane proximal domain (D1) exhibiting much higher activity than distal (D2) domain. Sequence alignment PTPα-D1 and -D2 D1 other receptor-like PTPs, modeling structures, identified non-conserved amino acids in PTPα-D2 that may account for its low activity. Mutation each residue (Val-536 or Glu-671) to conform invariant counterpart positively affected efficiency toward vitro...
Drosophila ninaC gene encodes myosin homologous proteins which are classified as III of the superfamily, yet physiological and biochemical function has not characterized. We report here that does exhibit protein kinase activity. The domain (MYOIIIPK) was expressed in baculovirus expression system purified to homogeneity. MYOIIIPK phosphorylated a number including p132 smooth muscle regulatory light chain (LC20), suggesting is multifunctional kinase. phosphoamino acid analysis revealed...
First-hits in the multi-hit process of leukemogenesis originate germline or hematopoietic stem cells (HSCs), yet leukemia-initiating (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution not been major focus investigation and remain poorly understood. Here mechanism was examined context Runx1 deficiency, frequent event. Lineage-negative isolated from bone marrow Runx1-haploinsufficient wild-type control mice...
Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the arrests, we find (1) repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other marks erased; (2) DNMT1 recurrently amplified, whereas...