A5040708190- Cell death mechanisms and regulation
- Virus-based gene therapy research
- CAR-T cell therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Mitochondrial Function and Pathology
- Inflammasome and immune disorders
- Autophagy in Disease and Therapy
- DNA Repair Mechanisms
- RNA Interference and Gene Delivery
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- interferon and immune responses
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- Endoplasmic Reticulum Stress and Disease
- S100 Proteins and Annexins
- Microtubule and mitosis dynamics
- NF-κB Signaling Pathways
- Hemoglobinopathies and Related Disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Cancer Research and Treatments
- Immune Response and Inflammation
- CRISPR and Genetic Engineering
- Neonatal Respiratory Health Research
Baylor College of Medicine
2015-2024
Texas Children's Hospital
2011-2024
Houston Methodist
2015
Methodist Hospital
2015
St. Jude Children's Research Hospital
2006-2011
La Jolla Institute for Immunology
2004-2006
University of Iowa
2005
Johannes Gutenberg University Mainz
2004
Trinity College Dublin
2000-2003
The tumor suppressor p53 exerts its anti-neoplastic activity primarily through the induction of apoptosis. We found that cytosolic localization endogenous wild-type or trans-activation-deficient was necessary and sufficient for directly activated proapoptotic Bcl-2 protein Bax in absence other proteins to permeabilize mitochondria engage apoptotic program. also released both multidomain BH3-only [Proapoptotic family share only third homology domain (BH3)] were sequestered by Bcl-xL....
The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates Bcl-2 proteins permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, p53, PUMA coordinates these distinct functions. After genotoxic stress, Bcl-xL sequestered p53. Nuclear caused expression of PUMA, which then displaced from allowing induce mitochondrial permeabilization. Mutant bound but...
During apoptosis, the mitochondrial outer membrane is permeabilized, leading to release of cytochrome c that activates downstream caspases. Mitochondrial permeabilization (MOMP) has historically been thought occur synchronously and completely throughout a cell, rapid caspase activation apoptosis. Using new imaging approach, we demonstrate MOMP not an all-or-nothing event. Rather, find minority mitochondria can undergo in stress-regulated manner, phenomenon term "minority MOMP." Crucially,...
Abstract The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and the highly immunosuppressive milieu tumors. To overcome these obstacles, we combined CAR-T an oncolytic virus armed chemokine RANTES cytokine IL15, reasoning that modified will both a direct lytic effect on infected malignant facilitate survival cells. Using neuroblastoma as tumor...
The mechanisms through which Caspase-2 leads to cell death are controversial. Here we show, using a combination of cell-free and culture-based approaches, that cleavage the Bcl-2-family protein Bid is required for induction apoptosis by Caspase-2. promoted cytochrome c release from mitochondria in presence cytosol wild-type, but not Bid-deficient, mouse embryonic fibroblasts (MEFs). Recombinant wild-type Bid, noncleavable mutant (D59E), restored release. Similarly, Bid-null MEFs were...
Caspase-2, one of the most evolutionarily conserved caspase family, has been implicated in maintenance chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2−/−) mice develop normally but show premature ageing-related traits when challenged by certain stressors, succumb to enhanced development aneuploidy. To test how caspase-2 protects against instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2−/− were exposed anti-mitotic drugs...
The PIDDosome (PIDD-RAIDD-caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response genotoxic stress. Yet studies of PIDD-deficient mice show that can proceed absence PIDD. Here we DNA damage induces assembly at least two distinct platforms caspase-2: a cytoplasmic RAIDD dependent but PIDD independent, and nucleolar requires both RAIDD. Furthermore, phosphoprotein nucleophosmin (NPM1) acts as scaffold essential nucleolus after damage....
Proteins possessing the caspase recruitment domain (CARD) motif have been implicated in pathways leading to activation of caspases or NF-κB context apoptosis inflammation, respectively. Here we report identification a novel protein, CARDINAL, that contains CARD and also exhibits high degree homology C terminus DEFCAP/NAC, recently described member Apaf-1/Nod-1 family. In contrast with majority proteins date, CARDINAL failed promote activation. Rather, potently suppressed associated...
Tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF family cytokines that promotes apoptosis and NF‐κB activation. Here we show recombinant hu‐TRAIL initiates activation multiple caspases, loss mitochondrial transmembrane potential, cleavage BID redistribution cytochrome c . However, whereas Bcl‐2 efficiently blocked UV radiation‐induced release consequent CEM cells, it failed to do either in context TRAIL treatment. Thus, engages death pathway at...
Abstract New therapies for glioblastoma (GBM) are needed, as five-year survival is <10%. The proteasome inhibitor marizomib (MRZ) has inhibitory and death-inducing properties unique from previous inhibitors such bortezomib (BTZ) not been well examined in GBM. We evaluated the mechanism of death vivo MRZ activation kinetics initiator caspases 2, 8 9 were assessed using chemical knockdown strategies to determine their contribution cell death. Blood brain barrier permeance inhibition by BTZ...