A5017270194- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Histone Deacetylase Inhibitors Research
- Hedgehog Signaling Pathway Studies
- RNA modifications and cancer
- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- Estrogen and related hormone effects
- CRISPR and Genetic Engineering
- Advanced biosensing and bioanalysis techniques
- Pancreatic function and diabetes
- FOXO transcription factor regulation
- Epigenetics and DNA Methylation
- Metabolism, Diabetes, and Cancer
- Thyroid Disorders and Treatments
- Growth Hormone and Insulin-like Growth Factors
- Light effects on plants
- Fatty Acid Research and Health
- Chemical Synthesis and Analysis
- Apelin-related biomedical research
- Circadian rhythm and melatonin
Scripps Research Institute
2019-2024
Scripps (United States)
2022-2024
Scripps Institution of Oceanography
2022-2024
Robert Bosch (Germany)
2023
University of Pennsylvania
2015-2021
Frederick Community College
2012
Center for Cancer Research
2011
Frederick National Laboratory for Cancer Research
2007
National Cancer Institute
2007
Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both core repressive component of the cell-autonomous clock regulator genes. Here, we show Rev-erbα modulates metabolism different genomic mechanisms. Clock control requires to bind directly genome at its cognate sites, where it competes with activating ROR TFs. By contrast, regulates genes primarily recruiting HDAC3 co-repressor sites which is tethered cell...
Abstract 5‐Methylcytosine (m 5 C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1‐7 in humans) of methyltransferases are capable installing the methyl group onto C position cytosines RNA. NSUNs implicated a wide range (patho)physiological processes, but selective and cell‐active inhibitors these enzymes lacking. Here, we use cysteine‐directed activity‐based profiling (ABPP) discover...
Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe set of stereo- and regiochemically defined spirocycle acrylamides the analysis these electrophilic "stereoprobes" human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared structurally related azetidine acrylamide stereoprobes, preferentially liganded specific cysteines on diverse...
The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion leads to fatty liver. To elucidate the underlying mechanism, here we report method cross-linking followed by mass spectrometry define high-confidence interactome in vivo that includes canonical NCoR-HDAC3 complex as well Prospero-related homeobox 1 protein (PROX1). PROX1 co-localize extensively on mouse liver genome, are co-recruited hepatocyte nuclear factor 4α (HNF4α). HDAC3-PROX1...
Ambient temperature influences the molecular clock and lipid metabolism, but impact of chronic cold exposure on circadian metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) including Srebp1 , master transcriptional regulator DNL, acquired high-amplitude rhythms BAT. These conditions activated mechanistic target rapamycin 1 (mTORC1), an inducer expression, engaged repressors REV-ERBα β...
Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role pancreatic β-cell function, but recent genetic study mice contradictory. Here we address the functional β-cells adult mice. An specific knockout was generated MIP-CreERT transgenic using Cre-loxP system....
Pioneer transcription factors (TFs) exhibit a specialized ability to bind and open closed chromatin, facilitating engagement by other regulatory involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively site-specifically TF, FOXA1, at cysteine (C258) within forkhead DNA-binding domain. We show these...
Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor activator binding thyroid hormone receptors (TRs), while the mechanism TH-dependent repression controversial. To address this, we generated mouse line in which endogenous TRβ1 was epitope-tagged allow...
Abstract In metastatic prostate cancer, most cases of resistance to direct AR inhibitors (ARi) are associated with a rebound in serum PSA implying reactivation. Resistance first generation ARi, like bicalutamide, has been linked amplification and is thought be caused by increased levels protein favoring the drug’s partial agonist activity. This agonism counteracts inhibition net effect incomplete antagonism. The phenomenon anti-androgen withdrawal syndrome documented early ARi supports this...
Smoothened is a critical component of the Hedgehog pathway that essential for stem cell renewal and dysregulated in many cancer types. We have found synthetic analogues second third intracellular loops smoothened to be potent inhibitors pathway. Palmitoylated peptides as short 10 residues inhibited melanoma cells growth with IC50 low nanomolar range. The compounds are promising drug candidates convenient tools solving mechanisms signaling.
Abstract Isolated protein motifs that are involved in interactions with their binding partners can be used to inhibit these interactions. However, peptides corresponding fragments tend have no defined secondary or tertiary structure the absence of scaffolding by rest molecule. This results low inhibitor potency. NMR and CD spectroscopy studies lipopeptide inhibitors Hedgehog pathway revealed membrane anchoring allows cell function as a scaffold facilitate folding short peptides. In addition,...
ABSTRACT Chemical probes are lacking for most human proteins. Covalent chemistry represents an attractive strategy expanding the ligandability of proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse Determining which these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing to infer functionality by quantifying their missense mutation cell proliferation. We show that resulting atlas,...
Summary Most human proteins lack chemical probes, and several large-scale generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such “binding-first” affect protein function, nonetheless, often remains unclear. Here, we describe a “function-first” proteomic strategy that uses size exclusion chromatography (SEC) assess the global impact of electrophilic on complexes cells. Integrating SEC data with cysteine-directed activity-based...
The Small Business Innovation Research (SBIR) program was created to stimulate technological innovation and business development at early stage companies in the United States. In its 21-year history, has channeled over $35 billion of public funds private businesses form approximately 137,000 grants. However, question whether SBIR funding effectively spurs new promotes commercialization remains controversial. Here, we review efforts answer this perform an independent analysis evaluate success...
A subset of Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M block N-Ras depalmitoylation, but lack specificity target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, potent selective covalent inhibitor the ABHD17 family depalmitoylases, show that this compound impairs depalmitoylation in human acute myeloid leukemia (AML)...
The longstanding concept of thyroid hormone (TH) action is summarized as the canonical switch model. This study adds important aspects TH to our current understanding, modifying this model a shift
Abstract 5‐Methylcytosine (m 5 C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1‐7 in humans) of methyltransferases are capable installing the methyl group onto C position cytosines RNA. NSUNs implicated a wide range (patho)physiological processes, but selective and cell‐active inhibitors these enzymes lacking. Here, we use cysteine‐directed activity‐based profiling (ABPP) discover...