A5002991984- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Genomics and Chromatin Dynamics
- Prostate Cancer Treatment and Research
- RNA Research and Splicing
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Animal Virus Infections Studies
- Cancer-related gene regulation
- T-cell and B-cell Immunology
- MicroRNA in disease regulation
- Cancer Research and Treatments
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Nuclear Receptors and Signaling
- Virus-based gene therapy research
- Biochemical and Molecular Research
- PARP inhibition in cancer therapy
- Genetics and Neurodevelopmental Disorders
- Telomeres, Telomerase, and Senescence
- RNA Interference and Gene Delivery
Thomas Jefferson University
2014-2025
Sidney Kimmel Cancer Center
2009-2023
University of Cambridge
2023
Sidney Kimmel Comprehensive Cancer Center
2013
Drexel University
2013
Johns Hopkins University
2013
Tampere University Hospital
2013
Tampere University
2013
Eli Lilly (United States)
2013
Schlosspark-Klinik
2013
Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose glutamine. Most remaining metabolites taken up by proliferating are not catabolized, but instead used as building blocks during anabolic macromolecular synthesis. Investigations phosphoinositol 3-kinase (PI3K) its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating uptake metabolism, rendering transformed cell addicted to for maintenance...
The c-Myc protein functions as a transcription factor to facilitate oncogenic transformation; however, the biochemical and genetic pathways leading transformation remain undefined. We demonstrate here that recently described cofactor TRRAP recruits histone acetylase activity, which is catalyzed by human GCN5 protein. Since function inhibited recruitment of deacetylase activity through Mad family proteins, these opposing activities are likely be responsible for antagonistic biological effects...
The c-MYC oncoprotein functions as a sequence-specific transcription factor. ability of to activate relies in part on the recruitment cofactor complexes containing histone acetyltransferases mammalian GCN5 (mGCN5)/PCAF and TIP60. In addition acetylating histones, these enzymes have been shown acetylate other proteins involved transcription, including factors. This study was initiated order determine whether is direct substrate mGCN5 We report here that mGCN5/PCAF TIP60 vivo. By using...
Initial studies of the mammalian hSAGA transcriptional coactivator complex identified acetyltransferase hGCN5/PCAF as only known enzymatic subunit. Recently we demonstrated that ubiquitin hydrolase USP22 comprises a second subunit hSAGA, and is required for activator-driven transcription. expressed with polycomb ligases in an 11 gene signature defines therapy-resistant tumors. At biochemical level, these Polycomb proteins function global repressors by catalyzing ubiquitylation histone H2A....
Abstract Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group tumor types, but its specificity underlying mechanisms action are not well defined. Here we show that USP22 is critical promoter lethal phenotypes acts by modulating nuclear receptor oncogenic signaling. In multiple xenograft models human cancer, modeling tumor-associated demonstrated controls androgen accumulation signaling,...
Significance The deubiquitylase USP22 is frequently overexpressed in cancer and contributes to tumorigenesis by driving cell cycle progression. Current models define as functional mediator of gene regulation chromatin modification, working within the SAGA transcriptional cofactor complex. Here we report a catalytic role for distinct from its well-characterized transcription regulatory capacity. directly stabilizes essential G1-cyclin, CCND1, protecting it proteasome-mediated degradation via...
The ATM-related TRRAP protein is a component of several different histone acetyltransferase (HAT) complexes but lacks the kinase activity characteristic other ATM family members. We identified novel function for this evolutionarily conserved domain in its requirement assembly functional HAT complex. Ectopic expression with mutation inhibits Myc-mediated oncogenic transformation. Myc-binding region maps to separable domain, and ectopic cell growth. These findings demonstrate that forms...
The yeast Ada and TBP class of Spt proteins interact in multiple complexes that are required for transcriptional regulation. We have identified Tra1p as a component these through tandem mass spectrometry analysis associate with Ngg1p/Ada3p. TRA1 is an essential gene encodes 3744-amino acid protein member group including the catalytic subunit DNA-dependent kinase, ATM TRRAP, carboxyl-terminal regions related to phosphatidylinositol 3-kinases. interaction between Ada/Spt components was...
We demonstrate that transformation-transactivation domain-associated protein (TRRAP) binding and the recruitment of histone H3 H4 acetyltransferase activities are required for transactivation a silent telomerase reverse transcriptase (TERT) gene in exponentially growing human fibroblasts by c-Myc or N-Myc protein. However, TRRAP c- is dispensable partial induction several basally expressed genes primary immortalized fibroblasts. Furthermore, c-Myc- N-Myc-mediated oncogenic transformation but...
The c- myc oncogene is among the most commonly overexpressed genes in human cancer. encodes a basic helix–loop–helix/leucine zipper (bHLH/LZ) transcription factor (c-MYC) that activates cascade of downstream targets ultimately mediate cellular transformation. Although large number are regulated by c-MYC, only few have been functionally linked to c-MYC-mediated By expression profiling, metastasis-associated protein 1 (MTA1) gene was identified here as target c-MYC oncoprotein primary cells,...