A5056605533- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Multiple Myeloma Research and Treatments
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
- Epigenetics and DNA Methylation
- MicroRNA in disease regulation
- DNA Repair Mechanisms
- Protein Degradation and Inhibitors
- Chromatin Remodeling and Cancer
- RNA modifications and cancer
- Genetic factors in colorectal cancer
- RNA Research and Splicing
- Protease and Inhibitor Mechanisms
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Endoplasmic Reticulum Stress and Disease
- Glycosylation and Glycoproteins Research
Dartmouth College
2011-2015
Imperial College London
2013-2015
Cotton (United States)
2015
University of Bath
2011
Significance Resistance to treatment with endocrine therapy occurs in ∼50% of all breast cancer patients. The pathway(s) leading drug resistance is ill-defined. We show that accessibility the genome altered drug-resistant compared responsive cells. This coincides overactivation NOTCH pathway transcription factor PBX1, a known target gene, required for growth therapy-resistant Accordingly, gene expression signature based on NOTCH-PBX1 activity can discriminate priori patients are or not therapy.
Proteasomes degrade the majority of proteins in mammalian cells by a concerted action three distinct pairs active sites. The chymotrypsin-like sites are targets antimyeloma agents bortezomib and carfilzomib. Inhibitors trypsin-like site sensitize multiple myeloma to these agents. Here we describe systematic effort develop inhibitors with improved potency cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), fluorescent activity-based probe for...
Proteasome inhibitor resistance is a challenge for myeloma therapy. Bortezomib targets the β5 and β1 activity, but not β2 activity of proteasome. Bortezomib-resistant cells down-regulate activation status unfolded protein response, up-regulate proteasome activity. To improve inhibition in bortezomib-resistant to achieve more efficient UPR activation, we have developed LU-102, selective LU-102 inhibited intact at low micromolar concentrations without relevant co-inhibition subunits. In...