A5080267048- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Cancer Research and Treatments
- Cancer-related molecular mechanisms research
- Polyomavirus and related diseases
- DNA Repair Mechanisms
- Bacteriophages and microbial interactions
- Virus-based gene therapy research
- RNA Research and Splicing
- Cell death mechanisms and regulation
- Plant Virus Research Studies
- Protein Degradation and Inhibitors
- interferon and immune responses
- Ferroptosis and cancer prognosis
- Genomics and Chromatin Dynamics
- Cancer, Lipids, and Metabolism
- Cancer Genomics and Diagnostics
- HIV Research and Treatment
- Microtubule and mitosis dynamics
- Cancer, Hypoxia, and Metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Molecular Biology Techniques and Applications
- Cell Image Analysis Techniques
Columbia University
2016-2025
Columbia University Irving Medical Center
1996-2024
National Center on Addiction and Substance Abuse at Columbia University
2022-2023
Fundación Instituto Leloir
2013
Consejo Nacional de Investigaciones Científicas y Técnicas
2013
New York Proton Center
2012
Howard Hughes Medical Institute
1990-2011
Carnegie Mellon University
2011
Institute of Molecular Biology and Biophysics
2011
Cancer Research Institute
2001
DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional mechanisms. Here we show that phosphorylation of human at serine 15 occurs after DNA damage and this leads reduced interaction with its negative regulator, the oncoprotein MDM2, in vivo vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), demonstrate serines 37 impairs ability MDM2 inhibit p53-dependent transactivation. We present evidence these effects are most likely due a conformational...
The ATM protein, encoded by the gene responsible for human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. shares a phosphoinositide 3-kinase–related domain with proteins, some of them protein kinases. A wortmannin-sensitive kinase activity was associated endogenous or recombinant and abolished structural mutations. In vitro substrates included translation repressor PHAS-I p53 protein. phosphorylated in on single residue, serine-15, which is...
The tumor-suppressor gene p53 is altered by missense mutation in numerous human malignancies. However, the biochemical properties of and effect on these are unclear. A DNA sequence was identified that binds specifically to wild-type protein vitro. As few as 33 base pairs were sufficient confer specific binding. Certain guanines within this 33-base pair region critical, methylation or their substitution with thymine-abrogated Human proteins containing either two mutations commonly found...
Randal S. Tibbetts, Kathryn M. Brumbaugh, Josie Williams, Jann N. Sarkaria, William A. Cliby, Sheau-Yann Shieh, Yoichi Taya, Carol Prives, and Robert T. Abraham Department of Pharmacology Cancer Cell Biology, Duke University, Durham, North Carolina 27710 USA; Division Oncology Research, Mayo Clinic Foundation, Rochester, Minnesota 55902 Biological Sciences, Columbia New York, York 10027 National Center Research Institute, Tokyo, Japan
Upon DNA damage, the amino terminus of p53 is phosphorylated at a number serine residues including S20, site that particularly important in regulating stability and function protein. Because no known kinase has been identified can modify this site, HeLa nuclear extracts were fractionated S20 phosphorylation was followed. We discovered activity copurifies with human homolog Schizosaccharomyces pombe checkpoint kinase, Chk1 (hCHK1). confirmed recombinant hCHK1, but not kinase-defective version...
It is well established that induction of the p53 tumor suppressor protein in cells can lead to either cell cycle arrest or apoptosis. To further understand features contribute these responses several p53-null Saos2 and H1299 lines were generated express wild-type mutant forms p53, cyclin-dependent kinase inhibitor p21/WAF1, under a tetracycline-regulated promoter. Our results show cellular level dictate response such lower levels result whereas higher apoptosis; nevertheless, DNA damage...
It has been proposed that the functions of cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27Kip1 are limited to cell cycle control at G1/S-phase transition in maintenance cellular quiescence. To test validity this hypothesis, p21 was expressed a diverse panel lines, thus isolating effects activity from pleiotropic upstream signaling pathways normally induce expression. The data show physiological levels accumulation, p21, addition its role negatively regulating G1/S transition,...
We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), key enzyme in conversion of glutamine to glutamate, and thereby regulator glutathione (GSH) synthesis energy production. GLS2 expression is induced response DNA damage or oxidative stress p53-dependent manner, associates with the promoter. Elevated facilitates metabolism lowers intracellular reactive oxygen species (ROS) levels, resulting an overall decrease oxidation as determined by measurement 8-OH-dG...
The adenovirus E1A oncogene activates p53 through a signaling pathway involving the retinoblastoma protein and tumor suppressor p19 ARF . ability of to induce its transcriptional targets is severely compromised in -null cells, which remain resistant apoptosis following serum depletion or adriamycin treatment. Reintroduction restores accumulation resensitizes cells apoptotic signals. Therefore, functions as part p53-dependent failsafe mechanism counter uncontrolled proliferation. Synergistic...
Oncogenic ras provokes a senescent-like arrest in human diploid fibroblasts involving the Rb and p53 tumor suppressor pathways. To further characterize this response, we compared gene expression patterns between -arrested quiescent IMR90 fibroblasts. One of genes up-regulated during -induced was promyelocytic leukemia (PML) protein, potential that encodes component nuclear structures known as oncogenic domains (PODs). PML levels increased both replicative senescence, leading to dramatic...
p53 can be isolated from cells in a form that is inert for binding to DNA but stimulated dramatically by phosphorylation, antibody binding, or short single strands of DNA. This suggests upon genotoxic stress, convert latent one active binding. Surprisingly, we observed as effective activating transcription vitro p53. We found HeLa nuclear extracts stimulate and have purified them p53-stimulating protein determined the product Ref-1 gene. Interestingly, dual function both regulate redox state...
The p53 protein is related by sequence homology and function to the products of two other genes, p63 p73, that each encode several isoforms. We others have discovered previously certain tumor-derived mutants can associate inhibit transcriptional activation α β isoforms p73. In this study we extended these observations show in transfected cells a number mutant proteins could bind down-regulate not only p73 (p73α, -β, -γ, -δ) but also (p63α -γ; ΔNp63α -γ). Moreover, correlation existed between...
The p53 tumor suppressor protein, found mutated in over 50% of all human tumors, is a sequence-specific transcriptional activator. Recent studies have identified relative, termed p73. We were interested determining the relative abilities wild-type and mutant forms p73α -β isoforms to transactivate various p53-responsive promoters. show that both p73β activate transcription reporters containing number promoters p53-null cell line H1299. However, significant differences observed between p73...