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Activation of Apoptosis Signalling Pathways by Reactive Oxygen Species

Reactive oxygen species

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells In addition, spermidine administration potently inhibited oxidative stress in ageing mice In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity

Induction of autophagy by spermidine promotes longevity

Apoptosis is a critically important biological process that plays an essential role in cell fate and homeostasis. An important component of the apoptotic pathway is the family of proteins commonly known as the B cell lymphoma-2 (Bcl-2). The primary role of Bcl-2 family members is the regulation of apoptosis. Although the structure of Bcl-2 family of proteins was reported nearly 10 years ago, however, it still surprises us with its structural and functional complexity and diversity. A number of studies have demonstrated that Bcl-2 family influences many other cellular processes beyond apoptosis which are generally independent of the regulation of apoptosis, suggesting additional roles for Bcl-2. The disruption of the regulation of apoptosis is a causative event in many diseases. Since the Bcl-2 family of proteins is the key regulator of apoptosis, the abnormalities in its function have been implicated in many diseases including cancer, neurodegenerative disorders, ischemia and autoimmune diseases. In the past few years, our understanding of the mechanism of action of Bcl-2 family of proteins and its implications in various pathological conditions has enhanced significantly. The focus of this review is to summarize the current knowledge on the structure and function of Bcl-2 family of proteins in apoptotic cellular processes. A number of drugs have been developed in the past few years that target different Bcl-2 members. The role of Bcl-2 proteins in the pathogenesis of various diseases and their pharmacological significance as effective molecular therapeutic targets is also discussed.

The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update.

Anti-apoptosis and cell survival: A review

Expression of human Bax, a cardinal regulator of mitochondrial membrane permeabilization, causes death in yeast. We screened a human cDNA library for suppressors of Bax-mediated yeast death and identified human 14-3-3β/α, a protein whose paralogs have numerous chaperone-like functions. Here, we show that, yeast cells expressing human 14-3-3β/α are able to complement deletion of the endogenous yeast 14-3-3 and confer resistance to a variety of different stresses including cadmium and cycloheximide. The expression of 14-3-3β/α also conferred resistance to death induced by the target of rapamycin inhibitor rapamycin and by starvation for the amino acid leucine, conditions that induce autophagy. Cell death in response to these autophagic stimuli was also observed in the macroautophagic-deficient atg1Δ and atg7Δ mutants. Furthermore, 14-3-3β/α retained its ability to protect against the autophagic stimuli in these autophagic-deficient mutants arguing against so called ‘autophagic death’. In line, analysis of cell death markers including the accumulation of reactive oxygen species, membrane integrity and cell surface exposure of phosphatidylserine indicated that 14-3-3β/α serves as a specific inhibitor of apoptosis. Finally, we demonstrate functional conservation of these phenotypes using the yeast homolog of 14-3-3: Bmh1. In sum, cell death in response to multiple stresses can be counteracted by 14-3-3 proteins.

/pdf/14-3-3-protects-against-stress-induced-apoptosis-416ao4jf2a.pdf

14-3-3 Protects against stress-induced apoptosis

Evidence for a second messenger function of dUTP during Bax mediated apoptosis of yeast and mammalian cells

Genetically programmed cell death (PCD) mechanisms, including apoptosis, are important for the survival of metazoans since it allows, among things, the removal of damaged cells that interfere with normal function Cell death due to PCD is observed in normal processes such as aging and in a number of pathophysiologies including hypoxia (common causes of heart attacks and strokes) and subsequent tissue reperfusion Conversely, the loss of normal apoptotic responses is associated with the development of tumours So far, limited success in preventing unwanted PCD has been reported with current therapeutic approaches despite the fact that inhibitors of key apoptotic inducers such as caspases have been developed Alternative approaches have focused on mimicking anti-apoptotic processes observed in cells displaying increased resistance to apoptotic stimuli Hormesis and pre-conditioning are commonly observed cellular strategies where sublethal levels of pro-apoptotic stimuli lead to increased resistance to higher or lethal levels of stress Increased expression of anti-apoptotic sequences is a common mechanism mediating these protective effects The relevance of the latter observation is exemplified by the observation that transgenic mice overexpressing anti-apoptotic genes show significant reductions in tissue damage following ischemia Thus strategies aimed at increasing the levels of anti-apoptotic proteins, using gene therapy or cell penetrating recombinant proteins are being evaluated as novel therapeutics to decrease cell death following acute periods of cell death inducing stress In spite of its functional and therapeutic importance, more is known regarding the processes involved in apoptosis than anti-apoptosis The genetically tractable yeast Saccharomyces cerevisiae has emerged as an exceptional model to study multiple aspects of PCD including the mitochondrial mediated apoptosis observed in metazoans To increase our knowledge of the process of anti-apoptosis, we screened a human heart cDNA expression library in yeast cells undergoing PCD due to the conditional expression of a mammalian pro-apoptotic Bax cDNA Analysis of the multiple Bax suppressors identified revealed several previously known as well as a large number of clones representing potential novel anti-apoptotic sequences Here we will discuss the nature and function of the anti-apoptotic sequences as well as the fact that screens such as these provide greater insight into the processes of anti-apoptosis as well as serving to further uncover the functional similarities between yeast and human PCD

/pdf/untangling-the-roles-of-anti-apoptosis-in-regulating-28y7k6aq9e.pdf

Liam Portt

Papers

Anti-apoptosis and cell survival: A review

14-3-3 Protects against stress-induced apoptosis

Evidence for a second messenger function of dUTP during Bax mediated apoptosis of yeast and mammalian cells

Untangling the Roles of Anti-Apoptosis in Regulating Programmed Cell Death using Humanized Yeast Cells.