A5069808553- Cancer-related Molecular Pathways
- Immunotherapy and Immune Responses
- Epigenetics and DNA Methylation
- vaccines and immunoinformatics approaches
- T-cell and Retrovirus Studies
- Neuroblastoma Research and Treatments
- Cancer Research and Treatments
- Immune Response and Inflammation
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Cancer therapeutics and mechanisms
- Cell death mechanisms and regulation
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Cancer Genomics and Diagnostics
- NF-κB Signaling Pathways
- Virus-based gene therapy research
- Telomeres, Telomerase, and Senescence
- Genomics and Chromatin Dynamics
- Chromosomal and Genetic Variations
- RNA Interference and Gene Delivery
Kola Science Centre
2014-2024
Geological Institute
2014-2024
Roswell Park Comprehensive Cancer Center
2015-2024
Frederick National Laboratory for Cancer Research
2023
Cancer Genetics (United States)
2010-2023
National Cancer Institute
2023
Wake Forest University
2021
Buffalo BioLabs
2014-2021
Abcombi Biosciences (United States)
2016-2020
Cleveland BioLabs (United States)
2007-2016
Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage normal tissues during treatment p53-deficient tumors. To test this possibility, small molecule was isolated its ability reversibly block p53-dependent transcriptional activation apoptosis. This compound, pifithrin-alpha, protected mice...
The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates signaling mechanism used by tumor cells to suppress can protect healthy from the harmful effects radiation. We studied CBLB502, polypeptide derived Salmonella flagellin binds Toll-like receptor 5 (TLR5) and nuclear factor–κB signaling. A single injection CBLB502 before lethal total-body irradiation protected mice both gastrointestinal...
Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-κB and triggers an innate immune response invading pathogen. To elucidate structural basis mechanistic implications of TLR5-flagellin recognition, we determined crystal structure zebrafish TLR5 (as a variable lymphocyte hybrid protein) in complex with D1/D2/D3 fragment Salmonella flagellin, FliC, at 2.47 angstrom resolution. interacts primarily three helices FliC D1 domain using...
Constitutive p16 Ink4a expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs).Recent reports attributed improvement the healthspan aged mice following -positive cell killing to eradication accumulated SCs.However, detection /SAβG-positive macrophages in adipose tissue old and peritoneal cavity young animals injection alginate-encapsulated SCs has raised concerns about exclusivity these markers for SCs.Here we report that...
Senescent cells (SCs) have been considered a source of age-related chronic sterile systemic inflammation and target for anti-aging therapies. To understand mechanisms controlling the amount SCs, we analyzed phenomenon rapid clearance human senescent fibroblasts implanted into SCID mice, which can be overcome when SCs were embedded alginate beads preventing them from immunocyte attack. identify putative SC killers, content cell populations in lavage capsules formed around SC-containing beads....
The circadian clock controls many physiological parameters including immune response to infectious agents, which is mediated by activation of the transcription factor NF-κB. It widely accepted that regulation based on periodic changes in gene expression are triggered transcriptional activity CLOCK/BMAL1 complex. Through use a mouse model system we show daily variations intensity NF-κB variety immunomodulators core protein CLOCK, can up-regulate NF-κB–mediated absence BMAL1; moreover, BMAL1...
Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates without causing DNA damage), we have previously identified cell lines in which caused quiescence. Importantly, by actively suppressing the senescence program (while still cycle arrest). Noteworthy, these cells inhibited mTOR (mammalian Target Rapamycin) pathway, is known to be involved program. Here showed shRNA-mediated knockdown TSC2, a negative regulator...
NF-kappaB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe NF-kappaB regulatory pathway that is driven by reversible lysine methylation the p65 subunit, carried out methylase, nuclear receptor-binding SET domain-containing protein 1 (NSD1), demethylase, F-box leucine-rich repeat 11 (FBXL11). Overexpression FBXL11 inhibits activity, high level NSD1 activates reverses inhibitory effect FBXL11, whereas reduced expression decreases activation....
Significance The accumulation of senescent cells over a lifetime causes age-related pathologies; however, the inability to reliably identify in vivo has hindered clinical efforts employ this knowledge as means ameliorate or reverse aging. Here, we describe reporter allele, p16 tdTom , enabling identification and isolation featuring high-level activation INK4a promoter. Our findings provide an insight into functional molecular characteristics -activated vitro vivo. We show that such...
The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss proliferative potential and senescent morphology). can also cause reversible arrest without morphology, which has usually been interpreted as failure to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression by p53. In previous studies, was masked cell cycle arrest. Here, separated these two activities inducing through overexpression p21 then testing the...
Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes interspersed tandem repeats. Here we show that the tumor suppressor protein p53 cooperates DNA methylation to maintain silencing a large portion mouse genome. Massive transcription major short, nuclear elements (SINEs) B1 B2, both strands near-centromeric satellite DNAs consisting repeats, multiple species noncoding RNAs was observed in p53-deficient but not wild-type fibroblasts treated...
We investigated the dynamic properties of organism state fluctuations along individual aging trajectories in a large longitudinal database CBC measurements from consumer diagnostics laboratory. To simplify analysis, we used log-linear mortality estimate variables as single quantitative measure process, henceforth referred to indicator (DOSI). observed, that age-dependent population DOSI distribution broadening could be explained by progressive loss physiological resilience measured...
The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and mutant mice demonstrate striking differences in their response the anticancer drug cyclophosphamide (CY). While sensitivity varies greatly, depending on time administration, Clock Bmal1 knockout are highly sensitive treatment at all times tested. On contrary, with loss-of-function mutations Cryptochrome (Cry1-/-Cry2-/- double knockouts) were more resistant CY...
Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying p53-responsive reporter. Among the compounds isolated were derivatives 9-aminoacridine (9AA), including antimalaria drug quinacrine, strongly induced p53 function and other types cancer cells....
Chronic inflammation is known to promote cancer, suggesting that negative regulation of likely be tumor suppressive. We found p53 a general inhibitor acts as an antagonist nuclear factor kappaB (NFkappaB). first observed striking similarities in global gene expression profiles human prostate cancer cells LNCaP transduced with inhibitory genetic element or treated TNF, inhibits transcription TNF-inducible genes are largely regulated by NFkappaB. Consistently, ectopically expressed...
Mammalian CLOCK and BMAL1 are two members of bHLH-PAS-containing family transcription factors that represent the positive elements circadian autoregulatory feedback loop. In form a heterodimer, they drive from E-box enhancer in promoters responsive genes. We have examined abundance, posttranslational modifications, cellular localization endogenous ectopically expressed proteins. Nuclear/cytoplasm distribution was found to be under regulation. Analysis subcellular embryo fibroblasts mice...
The quinacrine-related compounds curaxins target multiple procancer pathways through FACT complex.