A5070994420- Signaling Pathways in Disease
- Trace Elements in Health
- Cardiac Fibrosis and Remodeling
- Histone Deacetylase Inhibitors Research
- Phosphodiesterase function and regulation
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- RNA Research and Splicing
- Antifungal resistance and susceptibility
- HER2/EGFR in Cancer Research
- RNA modifications and cancer
- Lung Cancer Treatments and Mutations
- Cardiovascular Function and Risk Factors
- Fungal and yeast genetics research
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- Tissue Engineering and Regenerative Medicine
- Chromium effects and bioremediation
- Sulfur Compounds in Biology
- Genomics, phytochemicals, and oxidative stress
- Macrophage Migration Inhibitory Factor
- Sphingolipid Metabolism and Signaling
- Drug Transport and Resistance Mechanisms
- Plant biochemistry and biosynthesis
Cogent (United Kingdom)
2024
Cogent Biosciences (United States)
2023-2024
University of Colorado Anschutz Medical Campus
2016-2022
Gilead Sciences (United States)
2009-2011
Triad National Security (United States)
2002-2006
University of California, Berkeley
2001-2002
University of Michigan
1993-2001
Wayne State University
1990
Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models heart failure (HF). However, since target ubiquitously, it is unclear whether this chromatin reader functions cell type-specific manner control pathological myocardial fibrosis. Furthermore, molecular mechanisms by which stimulates transcriptional program for remain unknown. Objective: We sought test hypothesis that a cell-autonomous and...
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal–regulating kinase 1 (ASK1) a widely expressed redox-sensitive serine threonine that activates p38 c-Jun N-terminal (JNK) mitogen-activated protein kinases, induces apoptotic, inflammatory, fibrotic signaling in settings oxidative stress. We describe the discovery characterization potent selective small-molecule inhibitor ASK1, GS-444217, demonstrate therapeutic potential ASK1 inhibition to...
The essential yet toxic nature of copper demands tight regulation the homeostatic machinery to ensure that sufficient is present in cell drive biochemical processes prevent accumulation levels. In Saccharomyces cerevisiae, nutritional sensor Mac1p regulates copper-dependent expression high affinity Cu(I) uptake genesCTR1, CTR3, and FRE1, while Ace1p transcriptional activation detoxification genes CUP1, CRS5, SOD1 response copper. this study, we characterized tandem pathways chronic presence...
Gene expression in response to heat shock is mediated by the transcription factor (HSF), which yeast harbors both amino- and carboxyl-terminal transcriptional activation domains. Yeast cells bearing a truncated form of HSF domain has been deleted [HSF(1-583)] are temperature sensitive for growth at 37°C, demonstrating requirement this sustained viability during thermal stress. Here we demonstrate that HSF(1-583) undergo reversible cell cycle arrest 37°C G2/M phase exhibit marked reduction...
Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti‐hypertrophic action of class HDACs is overcome by signals that promote their phosphorylation‐dependent nuclear export. Several kinases have been shown to phosphorylate HDACs, including calcium/calmodulin‐dependent protein kinase (CaMK), D (PKD) and G protein‐coupled receptor (GRK). However, the identity kinase(s) responsible for phosphorylating during hypertrophy has remained...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTtRNA-guanine transglycosylase from Escherichia coli: Gross tRNA structural requirements for recognitionAlan W. Curnow, Fan Lu Kung, Keith A. Koch, and George GarciaCite this: Biochemistry 1993, 32, 19, 5239–5246Publication Date (Print):May 18, 1993Publication History Published online1 May 2002Published inissue 18 1993https://pubs.acs.org/doi/10.1021/bi00070a036https://doi.org/10.1021/bi00070a036research-articleACS PublicationsRequest reuse...
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart proposed potential antihypertrophic mechanism with application failure therapy. As PKC previously immediate upstream activator of PKD, vs selectivity essential to understand effect models cardiac hypertrophy and failure. The present study describes modification HTS hit series prototype pan-PKD inhibitors routine 1000-fold selectivity. Example...
Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific deletion promotes spontaneous vascular remodeling loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, overexpression reduces plaque area preserves SMC contractile protein expression atherosclerosis blunts Ang II (angiotensin II)-induced pathological remodeling, suggesting...
Rapid transcriptional autoactivation of theCandida glabrata AMT1 copper metalloregulatory transcription factor gene is essential for survival in the presence high extracellular concentrations.Analysis interactions between purified recombinant protein and promoter metal regulatory element was carried out by a combination missing-nucleoside analysis, ethylation interference, site-directed mutagenesis, quantitative vitro DNA binding studies.The results these experiments demonstrate that...
The synthesis and biological evaluation of potent selective PKD inhibitors are described herein. compounds in the present study selectively inhibit among other putative HDAC kinases. blunt phosphorylation subsequent nuclear export HDAC4/5 response to diverse agonists. These further establish central role as an kinase enhance current understanding cardiac myocyte signal transduction. vivo efficacy a representative example compound on heart morphology is reported
Cortical bone stem cell (CBSC) therapy after myocardial infarction alters the inflammatory response to cardiac injury. We found that cortical induces a unique macrophage phenotype in vitro and can modulate macrophage/fibroblast cross talk.
Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated contribute >45% deaths in the Western world, including those cardiovascular diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability suppress activation across organ systems.High-content imaging cultured cardiac, pulmonary, and renal was used identify nontoxic compounds that blocked induction markers response profibrotic stimulus, transforming...
Heart failure is the one of leading causes death in United States. a complex syndrome caused by numerous diseases, including severe myocardial infarction (MI). MI occurs after an occlusion cardiac artery causing downstream ischemia. followed remodeling involving extensive and fibrosis, which, if original insult or prolonged, can ultimately progress into heart failure. There no "cure" for because therapies to regenerate dead tissue are not yet available. Previous studies have shown that both...
Eukaryotic organisms ranging from yeast to humans maintain a large amount of genetic information in the highly compact folds chromatin, which poses DNA accessibility barrier rapid changes gene expression. The ability Candida glabrata survive copper insult requires transcriptional autoactivation AMT1 copper-metalloregulatory transcription factor gene. kinetics is greatly enhanced by homopolymeric (dA-dT) element (A16)-mediated nucleosomal for Amt1p metal response this promoter. Analysis...
The role of the Lys68*:Glu265 intersubunit salt bridge that is conserved (Csb) in all known aspartate aminotransferases (AATases), except those animal cytosolic, Ac (His68*:Glu265), and plant mitochondrial, Pm (Met68*:Gln265), origins, was evaluated Escherichia coli AATase. Two double-mutant cycles, to K68M/E265Q charge reversed K68E/E265K, were characterized with context dependence (C) impact (I) formalism, previously defined for functional chimeric analysis. Mutations Lys68* Glu265 fixed...
Transforming growth factor β (TGF-β) type I receptor (activin receptor-like kinase 5, ALK5) has been identified as a promising target for fibrotic diseases. To find novel inhibitor of ALK5, the authors performed high-throughput screen library 420,000 compounds using dephosphorylated ALK5. From primary hits 1521 compounds, 555 were confirmed. In total, 124 then selected follow-up based on their unique structures and other properties. Repeated concentration-response testing final interference...
The yeast Candida glabrata rapidly autoactivates transcription of the AMT1 gene in response to potentially toxic copper levels through copper-inducible binding Amt1 factor a metal element (MRE) within positioned nucleosome. Our previous studies have characterized role 16 bp homopolymeric dA:dT DNA structural facilitating rapid access promoter nucleosomal MRE. In this study, we used genetically more facile Saccharomyces cerevisiae identify additional cellular factors that are important for...
Abstract The PI3K pathway is a key cell cycle regulating that has an established role in tumor growth and development. Specifically, the H1047R helical domain mutations E542K/E545K of p110α subunit are known activating targeted by inhibitors under clinical investigation as well approved drugs. PI3Kα prevalent patients with breast, colorectal, lung, endometrial, numerous other cancers. inhibitor, alpelisib, shows promise for this class improvements progression-free survival HR+/Her2- breast...