Triggering and modulation of apoptosis by oxidative stress

Cell survival requires multiple factors, including appropriate proportions of molecular oxygen and various antioxidants. Although most oxidative insults can be overcome by the cell's natural defenses, sustained perturbation of this balance may result in either apoptotic or necrotic cell death. Numerous, recent studies have shown that the mode of cell death that occurs depends on the severity of the insult. Oxidants and antioxidants can not only determine cell fate, but can also modulate the mode of cell death. Effects of oxidative stress on components of the apoptotic machinery may mediate this modulation. This review will address some of the current paradigms for oxidative stress and apoptosis, and discuss the potential mechanisms by which oxidants can modulate the apoptotic pathway.     

Transcriptional regulators that differentially control dendrite and axon development

Neurons are the basic units of connectivity in the nervous system.As a signature feature,neurons form polarized structures:dendrites and axons,which integrate either sensory stimuli or inputs from upst...     

Cyclin-dependent kinase inhibitors,roscovitine and purvalanol,induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells

Roscovitine (Rosc) and purvalanol (Pur) are competitive inhibitors of cyclin-dependent kinases (CDKs) by targeting their ATP-binding pockets. Both drugs are shown to be effective to decrease cell viability and dysregulate the ratio of pro- and anti-apoptotic Bcl-2 family members, which finally led to apoptotic cell death in different cancer cell lines in vitro. It was well established that Bcl-2 family members have distinct roles in the regulation of other cellular processes such as endoplasmic reticulum (ER) stress. The induction of ER stress has been shown to play critical role in cell death/survival decision via autophagy or apoptosis. In this study, our aim was to investigate the molecular targets of CDK inhibitors on ER stress mechanism related to distinct cell death types in time-dependent manner in HeLa cervical cancer cells. Our results showed that Rosc and Pur decreased the cell viability, cell growth and colony formation, induced ER stress-mediated autophagy or apoptosis in time-dependent manner. Thus, we conclude that exposure of cells to CDK inhibitors induces unfolded protein response and ER stress leading to autophagy and apoptosis processes in HeLa cervical cancer cells.     

Mitochondrion-targeted apoptosis regulators of viral origin

During coevolution with their hosts, viruses have "learned" to intercept or to activate the principal signal transducing pathways leading to cell death. A number of proteins from pathophysiologically relevant viruses are targeted to mitochondria and regulate (induce or inhibit) the apoptosis-associated permeabilization of mitochondrial membranes. Such proteins are encoded by human immunodeficiency virus 1, Kaposi's sarcoma-associated herpesvirus, human T-cell leukemia virus-1, hepatitis B virus, cytomegalovirus, and Epstein Barr virus, among others. Within mitochondria, such apoptosis regulators from viral origin can target distinct proteins from the Bcl-2 family and the permeability transition pore complex including the adenine nucleotide translocase, cyclophilin D, the voltage-dependent anion channel, and the peripheral benzodiazepine receptor. Thus, viral proteins can regulate apoptosis at the mitochondrial level by acting on a variety of different targets.     

Chromosome breakage by ethylenimines and related compounds

Primary roots ofPisum sativum andVicia faba were treated for 1/2 hour with several ethylenimines and related compounds. Root samples were removed periodically for several mitotic cycles, and squash preparations were made and scored for anaphase damage as indicated by bridges and fragments. It was observed that maximum damage did not appear until after a delay which varied from 2 to 3 mitotic cycles after treatment, then dropped off in some cases, and persisted in others. The mitotic delay was estimated to be about 3 hours inPisum, and 6–7 hours inVicia. This delay is attributed to one or more of the following: (1) the number of strands in a chromosome, (2) the unit of breakage, and (3) the type of assortment of the chromatids, whether random or not. Some chemicals were mutagenic, although they did not induce any detectable chromosome damage. Experiments in which 5-amino-uracil was used did not indicate that any particular stage of the mitotic cycle was especially susceptible to damage. Preliminary experiments with DNP show that ATP is required either for uptake or site binding of the chemicals before actual breakage.Results of investigations carried out under NIH grant CA 06865-04 and project 99, Michigan Agricultural Experiment Station, East Lansing. Published with the approval of the Director as Journal Article 4450. We wish to thank Mrs.Jill Oakley, MissCarole Belcher, Mr. B. N. Singh, andMr. Roosevelt Alcorn for technical assistance, andDr. Roger Hoopingarner for many helpful discussions.Post doctoral fellow, Department of Crop Science, Michigan State University, and Professor of Botany, deceased January 18, 1968.