Iron in milk powder and milk
- Document Type:
- Application
- Product Catalog Number:
- Multiple
- Product Catalog Name:
- Multiple
100-63-0
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COA 100630
- Document Type:
- Certificate of Analysis
- Product Catalog Number:
- 100630
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Small-molecule inhibitors of the protein methyltransferase SET7/9 identified in a high-throughput screen.
- Aberrant expression of chromatin-modifying enzymes (CMEs) is associated with a range of human diseases, including cancer. CMEs are now an important target area in drug discovery. Although the role that histone and protein (lysine) methyltransferases (PMTs) play in the regulation of transcription and cell growth is increasingly recognized, few small-molecule inhibitors of this class of enzyme have been reported. Here we describe an assay suitable for primary compound screening for the identification of PMT inhibitors. The assay followed the methylation of histones in the presence of the PMT SET7/9 and the radioactive cofactor S-adenosyl-methionine using scintillating microplates (FlashPlate) and was used to screen approximately 65 000 compounds (% coefficient of variation = 10%; Z' = 0.6). The hits identified from a library of more than 63 000 diverse small molecules included a series of rhodanine compounds with micromolar activity. A screen of the National Cancer Institute Diversity Set (2000 compounds) identified an orsein derivative that inhibited SET7/9 (~20 µM) and showed modest growth inhibition associated with the expected cellular phenotype of reduced histone methylation in a human tumor cell line. The assay represents a useful tool for the identification of inhibitors of PMT activity.
- Document Type:
- Reference
- Product Catalog Number:
- 06-599
- Product Catalog Name:
- Anti-acetyl-Histone H3 Antibody
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Mouse tissues that undergo neoplastic progression after K-Ras activation are distinguished by nuclear translocation of phospho-Erk1/2 and robust tumor suppressor response ...
- Mutation of K-Ras is a frequent oncogenic event in human cancers, particularly cancers of lungs, pancreas, and colon. It remains unclear why some tissues are more susceptible to Ras-induced transformation than others. Here, we globally activated a mutant oncogenic K-Ras allele (K-Ras(G12D)) in mice and examined the tissue-specific effects of this activation on cancer pathobiology, Ras signaling, tumor suppressor, DNA damage, and inflammatory responses. Within 5 to 6 weeks of oncogenic Ras activation, mice develop oral and gastric papillomas, lung adenomas, and hematopoietic hyperproliferation and turn moribund. The oral, gastric, and lung premalignant lesions display activated extracellular signal-regulated kinases (Erk)1/2 and NF-κB signaling as well as activated tumor suppressor and DNA damage responses. Other organs such as pancreas, liver, and small intestine do not exhibit neoplastic progression within 6 weeks following K-Ras(G12D) activation and do not show a potent tumor suppressor response. Even though robust Erk1/2 signaling is activated in all the tissues examined, the pErk1/2 distribution remains largely cytoplasmic in K-Ras(G12D)-refractory tissues (pancreas, liver, and intestines) as opposed to a predominantly nuclear localization in K-Ras(G12D)-induced neoplasms of lung, oral, and gastric mucosa. The downstream targets of Ras signaling, pElk-1 and c-Myc, are elevated in K-Ras(G12D)-induced neoplastic lesions but not in K-Ras(G12D)-refractory tissues. We propose that oncogenic K-Ras-refractory tissues delay oncogenic progression by spatially limiting the efficacy of Ras/Raf/Erk1/2 signaling, whereas K-Ras-responsive tissues exhibit activated Ras/Raf/Erk1/2 signaling, rapidly form premalignant tumors, and activate potent antitumor responses that effectively prevent further malignant progression.
- Document Type:
- Reference
- Product Catalog Number:
- Multiple
- Product Catalog Name:
- Multiple