A5078928975- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Microtubule and mitosis dynamics
- Endoplasmic Reticulum Stress and Disease
- 14-3-3 protein interactions
- Genetic Syndromes and Imprinting
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Cellular transport and secretion
- Cancer-related Molecular Pathways
- Cell death mechanisms and regulation
- Autophagy in Disease and Therapy
- Axon Guidance and Neuronal Signaling
- Neuroscience and Neuropharmacology Research
- DNA Repair Mechanisms
- Reproductive Biology and Fertility
- Alzheimer's disease research and treatments
- Retinal Development and Disorders
- Prenatal Screening and Diagnostics
- Fungal and yeast genetics research
- Hippo pathway signaling and YAP/TAZ
- Nuclear Structure and Function
- ATP Synthase and ATPases Research
- Renal and related cancers
- Protease and Inhibitor Mechanisms
Johns Hopkins Medicine
2015-2025
Johns Hopkins University
2015-2025
Harvard University
2010
Duke University
2003-2009
Boston Children's Hospital
2007-2008
Centre for Cancer Biology
2006
Duke University Hospital
2005
Duke Medical Center
2005
Protein degradation is critical for brain function through processes that remain incompletely understood. Here, we investigated the in vivo of 20S neuronal membrane proteasome (NMP) Xenopus laevis tadpoles. With biochemistry, immunohistochemistry, and electron microscopy, demonstrated NMPs are conserved tadpole preferentially degrade activity–induced newly synthesized proteins vivo. Using calcium imaging optic tectum, showed acute NMP inhibition rapidly increased spontaneous activity,...
Dental enamel comprises interwoven arrays of extremely long and narrow crystals carbonated hydroxyapatite called rods. Amelogenin (AMELX) is the predominant extracellular matrix protein plays an essential role in formation (amelogenesis). Previously, we have demonstrated that full-length AMELX forms higher-order supramolecular assemblies regulate ordered mineralization vitro, as observed Phosphorylation sole phosphorylation site (Ser-16) vitro greatly enhances its capacity to stabilize...
Most human cancer cells are thought to acquire the ability divide beyond capacity of normal somatic through illegitimately activating gene hTERT, which encodes catalytic subunit telomerase.While telomerase reverse transcriptase (TERT) is conserved in most eukaryotes, mounting evidence suggests that C terminus protein may have functions unique higher eukaryotes.To search for domains responsible such functions, we assayed a panel tandem substitution mutations encompassing this region TERT...
The Cdc25 phosphatase promotes entry into mitosis through the removal of inhibitory phosphorylations on Cdc2 subunit Cdc2/CyclinB complex. During interphase, or after DNA damage, is suppressed by phosphorylation at Ser287 (Xenopus numbering; Ser216 human Cdc25C) and subsequent binding small acidic protein, 14-3-3. As reported recently, time mitotic entry, 14-3-3 protein removed from S287 dephosphorylated 1 (PP1). After initial activation consequent derepression Cdc2/CyclinB, further...
Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of neuronal membrane proteasome (NMP). We show that specific inhibition NMP on distal nerve fibers innervating mouse hind paw leads to reduction in mechanical pain sensitivity. Through investigating NMPs, demonstrate their somata proximal axons a subset dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments NMP-expressing DRGs...
The 19S regulatory particle (RP) associates with the 20S core (CP) to form 26S proteasome, an evolutionarily conserved holoenzyme that plays key roles in both physiological and pathological processes. Proteasome inhibitors target catalytic subunits within have proven be valuable research tools therapeutics for various cancers. Herein we report discovery of rapaprotin, a proteasome assembly inhibitor from our natural product-inspired hybrid macrocycle rapafucin library. Rapaprotin induces...
Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that each vital to human brain health and disease. Despite their importance, standardized approaches investigate proteasomes have not been universally adapted. Here, we describe pitfalls define straightforward orthogonal biochemical essential measure understand changes in proteasome composition activity the mammalian central nervous system. Through our experimentation brain, determined an abundance of...
Abstract Apoptotic signaling defects both promote tumorigenesis and confound chemotherapy. Typically, chemotherapeutics stimulate cytochrome c release to the cytoplasm, thereby activating apoptosome. Although cancer cells can be refractory release, many malignant also exhibit in c–induced apoptosome activation, further promoting chemotherapeutic resistance. We have found that breast display an unusual sensitivity apoptosis when compared with their normal counterparts. This sensitivity, not...
The neuronal membrane proteasome (NMP) degrades intracellular proteins into peptides that are released directly the extracellular space, whereby they stimulate neurons to promote signaling mechanisms remain unknown. Here, we demonstrate stimulation promotes NMP activity and, subsequently, enhanced production of peptides. We show these activity-dependent can rapidly N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx in neurons. This leads sustained phosphorylation well-defined...
Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression the developmental repressor Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote production mature hippocampal neurons mice expressing human amyloid precursor (hAPP mice), a model for familial AD produces high brain levels Aβ. was highly elevated hippocampi patients, indicating its potential...