ABSTRACT
Evidences show that eukaryotic mRNAs can perform protein translation through internal ribosome entry sites (IRES). 5'-Untranslated region of the mRNA encoding apoptotic protease-activating factor 1 (Apaf-1) contains IRES, and, thus, can be translated in a cap-independent manner. Effects of changes in protein translation pattern through rapamycin pretreatment on 4-(methylnitrosamino)-1-(3-pyridyl)-butanone(NNK, tobacco-specific lung carcinogen)-induced apoptosis in human bronchial epithelial cells were examined by caspase assay, FACS analysis, Western blotting, and transient transfection. Results showed that NNK induced apoptosis in concentration- and time-dependent manners. NNK-induced apoptosis occurred initially through cap-independent protein translation, which during later stage was replaced by cap-dependent protein translation. Our data may be pplicable as the mechanical basis of lung cancer treatment.
Subject(s)
Humans , Antibiotics, Antineoplastic/pharmacology , Apoptosis/drug effects , Apoptotic Protease-Activating Factor 1 , BH3 Interacting Domain Death Agonist Protein , Blotting, Western , Bronchi/metabolism , Carcinogens/pharmacology , Carrier Proteins/metabolism , Caspases/metabolism , Cytochromes c/metabolism , Dose-Response Relationship, Drug , Epithelial Cells/metabolism , Eukaryotic Initiation Factor-4E/metabolism , Flow Cytometry , Nitrosamines/pharmacology , Protein Biosynthesis , Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Cap-Binding Proteins/physiology , Sirolimus/pharmacology , Time Factors , bcl-2-Associated X ProteinABSTRACT
The effect of four alkylating agents (MMS, EMs, DMN, DEM), under various con centrations on mouse bone marrow erythrocytes, were studied by means of the micronucleus test. The results obtained were as follows: 1) The lethal doses on mice were MMS = 130 mg/kg/bw, EMS = 300 mg/kg/bw, DMN = 50 mg/kg/bw and DEN = 70 mg/kg/bw. 2) Micronuclei were easily seen and in different controls the micronulei were found a little over 0.1%. 3) The dose-effect relationship was obtained. In the MMS and EMS treated groups, incidences of micronulei were 0.45 to 2.56% and 0.4 to 2.1% respectively. 4) In the DMN and DEN treated groups, incidences varied between 0.15 to 0.90 % and 0.2 to 1.02% respectively. 5) Four alkylating agents were compared and discussed with respect to micro nucleus production from chromosomal aberrations.
Subject(s)
Female , Mice , Animals , Bone Marrow/ultrastructure , Carcinogens/pharmacology , Cell Nucleus/drug effects , Chromosome Aberrations , Erythrocytes/ultrastructure , Mesylates/pharmacology , Mutagens/pharmacology , Nitrosamines/pharmacologyABSTRACT
The ultrastructural alterations in rat liver by feeding NHM(nitrosohexamethylenemine). These are described at intervals of 10 days, 5 weeks, 11 weeks, 14 weeks, 19 weeks, and 22 weeks. The group at 5 and 11 weeks showed hyperplastic lesions but, no nuclear change. There were dilated rough endoplasmic reticulum with detached ribosomes, and alteration of mitochondria. The mitochondria showed a dense matrix which often included membranous materials. In the l4, 19, and 22 week groups, it showed nodular lesion which had atypical cells, and it was observed that the nucleus were enlarged and nucleoli were segregated. The bile canaliculi were dilated and contained dense materials.