A5072259650- Cancer Cells and Metastasis
- Pancreatic and Hepatic Oncology Research
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Cancer, Lipids, and Metabolism
- Radiomics and Machine Learning in Medical Imaging
- Cancer Treatment and Pharmacology
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Biochemical effects in animals
- Biochemical and Molecular Research
- Ion channel regulation and function
- Ion Channels and Receptors
- Tryptophan and brain disorders
- Advanced Glycation End Products research
- Connexins and lens biology
- Muscle Physiology and Disorders
- Protein Kinase Regulation and GTPase Signaling
- Congenital heart defects research
- Veterinary medicine and infectious diseases
- HER2/EGFR in Cancer Research
- Cancer Research and Treatments
- Retinoids in leukemia and cellular processes
- Cardiomyopathy and Myosin Studies
Saint Louis University
2024
Moffitt Cancer Center
2018-2023
La Jolla Institute for Immunology
2015-2019
Centre for Cellular and Molecular Biology
2010-2015
Council of Scientific and Industrial Research
2010-2012
Osmania University
2006-2010
STIM1 and STIM2 are endoplasmic reticulum (ER) membrane proteins that sense decreases in ER-luminal free Ca2+ and, through a conformational change the STIM cytoplasmic domain, control gating of plasma channel ORAI1. To determine how conveys signal from ER lumen to cytoplasm, we studied Ca2+-dependent engineered isolated membranes parallel, physiological activation these cells. We find conserved "sentinel" features CC1 region help prevent while is bound domains. Reduced drives concerted...
Significance Close appositions between the endoplasmic reticulum (ER) and plasma membrane in mammalian cells have essential roles cellular lipid metabolism cytoplasmic calcium signaling. Although recent investigations yielded considerable insight into structural basis for transfer at ER–plasma junctions, little is known about proteins that organize junctions Our data show ER protein transmembrane 110 (TMEM110) supports maintenance of competent signaling acts concert with other dynamic...
Abstract Stromal interaction molecule 1 (STIM1) monitors ER-luminal Ca 2+ levels to maintain cellular balance and support signalling. The prevailing view has been that STIM1 senses reduced ER through dissociation of bound from a single EF-hand site, which triggers dramatic loss secondary structure dimerization the luminal domain. Here we find domain 5–6 -binding sites, binding at these sites is energetically coupled controls switch second structured conformation rather than protein...
Abstract Purpose: Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency. Experimental Design: Global phosphoproteomics, screening of a chemical library FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities Results: phosphoproteomics revealed dependency driven by cyclin-dependent kinase (CDK) network. that, in KRas-driven pancreatic cancer...
Abstract Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery small molecule, KRB-456, binds G12D and inhibits growth pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed KRB-456 GDP-bound GCP-bound conformation by forming interactions with dynamic allosteric binding pocket within switch-I/II region. Isothermal titration calorimetry demonstrated...
Background Many bacterial surface exposed proteins mediate the host-pathogen interaction more effectively in presence of Ca2+. Leptospiral immunoglobulin-like (Lig) proteins, LigA and LigB, are containing Bacterial immunoglobulin like (Big) domains. The function which contain Big fold is not known. Based on possible similarities βγ-crystallin folds, we here explore important question whether Ca2+ binds to a domains, would provide novel functional role fold. Principal Findings We selected six...
Purpose: Glycated lens proteins are capable of producing reactive oxygen species (ROS), which, in turn, can oxidize tryptophan (Trp) into kynurenines. Indoleamine 2,3-dioxygenase (IDO), which is expressed many tissues and inducible by interferon-γ (IFN-γ), able to Trp These kynurenines modify and, fact, kynurenine adducts markedly increased lenses with age-related nuclear cataract. Therefore, it has been suggested that lenticular IDO involved diabetic cataractogenesis. The aim the present...
Glycemic-induced stress is a major culprit contributing to oxidative insult that has far-reaching effects in diabetic cataract worldwide. In an attempt prevent/delay cataract, many therapeutic agents have been identified, and among these, natural dietary sources gained pharmacological significance. Hence, we investigated the efficacy of methanolic garlic extract against Wistar rats. Methanolic scavenged transition metal ion-generated H(2)O(2) with IC(50) 768.8 +/- 1.76 mug/ml, showing its...
ABSTRACT Evaluating natural sources for anticataractous potential may lead to the development of safer and more effective agents. Keeping this in view, we have made an attempt investigate effect mustard (Brassica juncea) leaf extract (BJLE) on streptozotocin (STZ)-induced diabetic cataract Wistar rats. A daily oral dose BJLE at 250 500 mg/kg body weight was administered STZ-induced rats 8 weeks. Reversal changes associated with hyperglycemia, delayed progression maturation were observed two...
Facioscapulohumeral muscular dystrophy (FSHD) is a degenerative muscle disease caused by loss of epigenetic silencing and ectopic reactivation the embryonic double homeobox protein 4 gene (DUX4) in skeletal muscle. The p38 MAP kinase inhibitor losmapimod currently being tested FSHD clinical trials due to finding that inhibition suppresses DUX4 expression preclinical models. However, role regulating at different myogenic stages has not been investigated. We used genetic pharmacologic tools...
The folding and unfolding of structurally similar proteins belonging to a family have long been focus investigation the structure-(un)folding relationship. Such studies are yet reach consensus about whether domains follow common or different pathways. Members βγ-crystallin superfamily, which consists with limited sequence similarity from diverse life forms spanning microbes mammals, form an appropriate model system for exploring this relationship further. We selected new member, Crybg3_D3,...
Many members of the neuronal calcium sensor (NCS) protein family have a striking coexistence two characteristics, that is, N-myristoylation and cryptic EF-1 motif. We investigated rationale behind this correlation in sensor-1 (NCS-1) by restoring Ca2+ binding ability disabled loop appropriate mutations. The concurrence canonical considerably decreased overall affinity, conformational flexibility, functional activation downstream effecter molecules (i.e., PI4Kβ). Of particular note, induced...
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle wasting disease caused by misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression D4Z4 macrosatellite repeats recognized to cause DUX4 FSHD, factors promoting are unknown. Here, we show that SIX ( sine oculis ) factors, critical during embryonic development, differentiation, regeneration and homeostasis, key regulators expression FSHD cells. In this...
Facioscapulohumeral muscular dystrophy (FSHD) is a common and progressive muscle wasting disease that characterized by weakness often first noticed in the face, shoulder girdle upper arms before progressing to lower limb muscles. FSHD caused misexpression of Double Homeobox 4 (DUX4) transcription factor skeletal muscle. While epigenetic derepression D4Z4 macrosatellite repeats underlies DUX4 misexpression, our understanding complex transcriptional activation incomplete. To identify potential...
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<p>Supplementary Methods</p>
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