A5050128762- Cancer-related Molecular Pathways
- RNA modifications and cancer
- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- Cancer Research and Treatments
- RNA Research and Splicing
- Cancer, Hypoxia, and Metabolism
- Molecular Biology Techniques and Applications
- Bioactive Compounds and Antitumor Agents
- Cancer therapeutics and mechanisms
- Cancer, Lipids, and Metabolism
- Cell death mechanisms and regulation
- Microtubule and mitosis dynamics
- MicroRNA in disease regulation
- Virus-based gene therapy research
- Spectroscopy Techniques in Biomedical and Chemical Research
- DNA and Nucleic Acid Chemistry
- thermodynamics and calorimetric analyses
- Advanced Breast Cancer Therapies
- Genetic factors in colorectal cancer
- 3D Printing in Biomedical Research
City University of New York
2016-2025
Hunter College
2016-2025
The Graduate Center, CUNY
2015-2024
Cornell University
2017-2024
Northwestern University
2012
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
2012
Rutgers New Jersey Medical School
2012
Rutgers, The State University of New Jersey
2012
New York Proton Center
2012
Duke University
2010
The DNA from a wide variety of human tumors has sustained mutations within the conserved p53 coding regions. We have purified wild-type and tumor-derived mutant proteins expressed baculovirus vectors examined their interactions with SV40 DNA. Using DNAase I footprinting assays, we observed that both murine bind specifically to sequences adjacent late border viral replication origin. By contrast, failed these sequences. T antigen prevented interacting this region. These data show normal but...
It has been reported recently that the wild-type p53 gene product can positively regulate expression of a test adjacent to enhancer-promoter elements murine muscle-specific creatine kinase (MCK) gene. This discussion reports identification protein-specific DNA-binding element located within p53-responsive region MCK element. protein/DNA-binding defined by DNase I footprint analysis, which identified 50-bp region. sequence was sufficient confer responsiveness on heterologous minimal promoter....
J Bargonetti, Manfredi, X Chen, D R Marshak, and C Prives Department of Biological Sciences, Columbia University, New York, York 10027.
We have analyzed the size and structure of native immunopurified human p53 protein. By using a combination chemical crosslinking, gel filtration chromatography, zonal velocity gradient centrifugation, we determined that predominant form in such preparations is tetramer. The behavior purified gels sucrose gradients implies protein has an extended shape. Wild-type been shown to bind specifically sites cellular viral DNA. show this study by Southwestern ligand blotting analysis DNA-bound...
Wild-type p53 protein was shown to bind specifically DNA sequences within SV40 (Bargonetti et al. 1991), the human ribosomal gene cluster (RGC) (Kern 1991a), and murine muscle creatine kinase (MCK) (Zambetti 1992). However, a direct comparison of these three sites not performed. Here we demonstrate, by filter binding gel mobility-shift assays, that wild-type binds with similar affinities MCK RGC but less tightly site. We examined effects two candidate regulators function, large T antigen...
Mutant p53 impacts the expression of numerous genes at level transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 ( VEGFR2 ), primary functional VEGF that mediates cell vascularization, as a mutant transcriptional target in multiple breast cancer lines. Up-regulation role increasing cellular two-dimensional (2D) and three-dimensional (3D) culture conditions. binds near promoter start site plays maintaining an open conformation location. Relatedly,...
The majority of human tumors express mutant forms p53 at high levels, promoting gain oncogenic functions and correlating with disease progression, resistance to therapy unfavorable prognosis. accumulation in is attributed the ability evade degradation by proteasome, only currently recognized machinery for disruption. We report here that glucose restriction (GR) induces deacetylation, routing it via autophagy. Depletion leads, turn, robust autophagic activation cell death, while expression...
Abstract Radiation-induced gastrointestinal syndrome is a major complication and limiting factor for radiotherapy. Tumor suppressor p53 has protective role in radiation-induced toxicity. However, its underlying mechanism remains unclear. Here we report that regulating the IL12-p40/MHC class II signaling pathway critical by which protects against syndrome. inhibits expression of inflammatory cytokine IL12-p40, turn suppresses MHC on intestinal epithelial cells to suppress T cell activation...
Infrared spectra of myeloid leukemia (ML-1) cells are reported for derived from an asynchronous, exponentially growing culture, as well that were fractionated according to their stage within the cell division cycle. The observed results suggest cells' DNA is detectable by infrared spectroscopy mainly when in S phase, during replication DNA. In G1 and G2 phases, so tightly packed nucleus it appears opaque radiation. Consequently, nucleic acid spectral contributions phases would be mostly...
In cancer cells, the function of tumor suppressor protein p53 is usually blocked. Impairment pathway results in cells with endogenous overexpression Mdm2 via a naturally occurring single nucleotide polymorphism (SNP) mdm2 gene at position 309. Here we report that SNP309 inactivation chromatin-associated Mdm2-p53 complex without clearance by degradation. Nuclear accumulation after 6 h camptothecin, etoposide, or mitomycin C treatment, phosphorylated Ser15. Chromatin immunoprecipitation...
Abstract Introduction Estrogen receptor positive breast cancers often have high levels of Mdm2. We investigated if estrogen signaling in such occurred through an Mdm2 mediated pathway with subsequent inactivation p53. Methods examined the effect long-term 17β-estradiol (E2) treatment (five days) on p53-Mdm2 alpha (ERα) cancer cell lines that contain wild-type p53 (MCF-7 and ZR75-1). assessed influence by examining proliferation changes, activation transcription target genes, p53-chromatin...
The gain-of-function mutant p53 (mtp53) transcriptome has been studied, but, to date, no detailed analysis of the mtp53-associated proteome described. We coupled cell fractionation with stable isotope labeling amino acids in culture (SILAC) and inducible knockdown endogenous mtp53 determine mtp53-driven proteome. Our data highlight underappreciated biology that missense proteins R273H, R280K, L194F are tightly associated chromatin. Using SILAC tandem MS, we identified R273H expression...
Abstract Over 80% of triple-negative breast cancers (TNBC) express mutant p53 (mtp53) and some contain oncogenic gain-of-function (GOF) p53. We previously reported that GOF mtp53 R273H upregulates the chromatin association mini chromosome maintenance (MCM) proteins MCM2-7 PARP named this mtp53–PARP–MCM axis. In study, we dissected function between using a number different cell lines, patient-derived xenografts (PDX), tissue microarrays (TMA), The Cancer Genome Atlas (TCGA) database....
Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate replicating DNA and (PARP) protein. Combination drug treatment alkylating agent temozolomide talazoparib kills mtp53 expressing grown lines. We evaluated sensitivity combination of plus lung...
Plasmid pT181 DNA secondary structures have been analyzed in vitro by nuclease S1 digestion and vivo bromoacetaldehyde treatment. A cruciform structure occurring at the replication origin is greatly enhanced binding of plasmid-encoded initiator protein RepC. In a also existed origin. Its frequency formation was correlated with efficiency RepC utilization. These data suggest that extrusion involved initiation rolling-circle replication. neighboring influences conformation vivo.
Over 80% of triple negative breast cancers express mutant p53. Mutant p53 often gains oncogenic function suggesting that may be driven by protein type. To determine the chromatin targets this gain-of-function we used inducible knockdown endogenous mtp53 in MDA-MB-468 cells conjunction with stable isotope labeling amino acids cell culture and subcellular fractionation. We sequenced over 70,000 total peptides for each corresponding reciprocal data set were able to identify 3010 unique...
Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDMX occurs in estrogen receptor α-positive (ERα+) cancer triple-negative (TNBC). There are p53-independent influences MDMX, 80% TNBC express mutant p53 (mtp53). drives circulating tumor cells (CTCs) mice, but context-dependent on different subtypes expressing mtp53 have not been determined. To assess roles, we carried out knockdown orthotopic tumors MDA-MB-231 R280K ERα+ T47D L194F. The...
Abstract The tumor-suppressive function of p53 is frequently disrupted by mutations in cancers. Missense mutant (mutp53) protein often stabilizes and accumulates to high levels cancers promote tumorigenesis through the gain-of-function (GOF) mechanism. Currently, mechanism mutp53 accumulation GOF incompletely understood. Here, we identify lipogenic enzyme FASN as an important regulator GOF. interacts with enhance palmitoylation, which inhibits ubiquitination Blocking genetically or...