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PubMed2004

Mitochondrial fission proteins regulate programmed cell death in yeast.

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Adi3 is a Pdk1-interacting AGC kinase that negatively regulates plant cell death.

Bacterial speck disease in tomato is caused by Pseudomonas syringae pv. tomato. Resistance to this disease is conferred by the host Pto kinase, which recognizes P. s. pv. tomato strains that express the effector AvrPto. We report here that an AvrPto-dependent Pto-interacting protein 3 (Adi3) is a member of the AGC family of protein kinases. In mammals, AGC kinases are regulated by 3-phosphoinositide-dependent protein kinase-1 (Pdk1). We characterized tomato Pdk1 and showed that Pdk1 and Pto phosphorylate Adi3. Gene silencing of Adi3 in tomato causes MAPKKKalpha-dependent formation of necrotic lesions. Use of a chemical inhibitor of Pdk1, OSU-03012, also implicates Pdk1 and Adi3 in plant cell death regulation. Adi3 thus appears to function analogously to the mammalian AGC kinase protein kinase B/Akt by negatively regulating cell death via Pdk1 phosphorylation. We speculate that the negative regulatory function of Adi3 might be subverted by interaction with Pto/AvrPto, leading to host cell death that is associated with pathogen attack.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2005

High-throughput in planta expression screening identifies a class II ethylene-responsive element binding factor-like protein that regulates plant cell death and non-host resistance.

We performed high-throughput screening using the potato virus X (PVX) system to overexpress Nicotiana benthamiana genes in planta and identify positive regulators of cell death. This screening identified NbCD1, a novel class II ethylene-responsive element binding factor (ERF), as a potent inducer of the hypersensitive response (HR)-like cell death. NbCD1 expression was induced by treatments with INF1 elicitor and a non-host pathogen Pseudomonas cichorii. NbCD1 exhibited transcriptional repressor activity through its EAR motif, and this motif was necessary for NbCD1 to cause cell death. We identified 58 genes that displayed altered transcription following NbCD1 overexpression. NbCD1 overexpression downregulated the expression of HSR203, a negative regulator of hypersensitive death. Conditional expression of NbCD1 in Arabidopsis also caused cell death, indicating that NbCD1 downstream cascades are conserved in dicot plants. To further confirm the role of NbCD1 in defense, we used virus-induced gene silencing to demonstrate that NbCD1 is required for non-host resistance of N. benthamiana to the bacterial pathogen P. cichorii. Our data point to a model of transcriptional regulatory cascades. NbCD1 positively regulates cell death and contributes to non-host resistance, possibly by downregulating the expression of other defense response genes.

Amino Acid Sequence↗
PubMed1995

Colony-stimulating factors regulate programmed cell death of rat microglia/brain macrophages in vitro.

Programmed cell death of activated microglia appears to be one mechanism how steady state of microglia is achieved in vivo. Programmed cell death of microglia might result either from the downregulation of microglial mitogens/survival factors or from signals which directly induce microglial cell death. To further elucidate the mechanisms regulating programmed cell death in microglia, growth factor and cytokine dependence of microglial proliferation and cell death have been examined in vitro in microglia/brain macrophage cultures established from neonatal rat brain. Microglial proliferation was assessed by PCNA labelling and DNA fragmentation by the TUNEL technique in the presence or absence of several cytokines including IL-1, IL-6, TGF beta 1, TNF alpha, M-CSF and GM-CSF. Results of TUNEL labellings were supplemented by gel electrophoretic analysis of DNA extracted from cultured microglia which showed laddering of DNA fragments. Of all cytokines/growth factors tested, GM-CSF and M-CSF were not only the strongest microglial mitogens but, moreover, withdrawal of M-CSF or GM-CSF significantly enhanced rates of microglial cell death by DNA fragmentation. Expression of microglial growth factors, in particular colony-stimulating factors, may thus be instrumental in controlling steady states of microglia in the injured nervous system.

Animals↗
PubMed2004

Regulation of cell death in the lymphoid system by Bcl-2 family proteins.

Programmed cell death is an ordered process that is essential for the normal development and homeostasis of an organism. Dysregulation of this programmed pathway, resulting in either excess cell numbers or unscheduled cell death, underlies a number of disease states. Bcl-2 family proteins play a key role in regulating cell death and survival, and a number of studies have demonstrated their role as important regulators of cell fate in the lymphoid system. Mice that are genetically deficient or overexpress various Bcl-2 family proteins have provided important clues regarding their roles in lymphocyte development, progression of lymphoid tumors and analogous human disorders. In addition, lymphotropic viruses may trigger cell proliferation and inhibit cell death with the help of their own Bcl-2 homologues. Comparing the shared and distinct functions of viral and cellular Bcl-2-related proteins yields new insight into their fundamental mechanisms.

Animals↗
PubMed2000

Drug discovery opportunities from apoptosis research.

Cell suicide is a normal process that participates in a wide variety of physiological processes, including tissue homeostasis, immune regulation, and fertility. Physiological cell death typically occurs by apoptosis, as opposed to necrosis. Defects in apoptotic cell-death regulation contribute to many diseases, including disorders associated with cell accumulation (e.g. cancer, autoimmunity, inflammation and restenosis) or where cell loss occurs (e.g. stroke, heart failure, neurodegeneration, AIDS and osteoporosis). At the center of the apoptosis machinery is a family of intracellular proteases, known as 'caspases', that are responsible directly or indirectly for the morphological and biochemical events that characterize apoptosis. Multiple positive and negative regulators of these cell-death proteases have been discovered in the genomes of mammals, amphibians, insects, nematodes, and other animal species, as well as a variety of animal viruses. Inputs from signal-transduction pathways into the core of the cell-death machinery have also been identified, demonstrating ways of linking environmental stimuli to cell-death responses or cell-survival maintenance. Knowledge of the molecular mechanisms of apoptosis has provided important insights into the causes of multiple diseases where aberrant cell-death regulation occurs and has revealed new approaches for identifying small-molecule drugs for more effectively treating these illnesses.

Animals↗
PubMedDate not supplied

Molecular regulation of cell death and therapeutic strategies for cell death induction in prostate carcinoma.

Many of the common molecular alterations associated with prostate cancer progression involve genes known to regulate cell death susceptibility. The significance of these molecular events is discussed in the context of developing and implementing new strategies designed to restore cell death susceptibility in prostate cancer cells and overcome therapeutic resistance.

Apoptosis↗
PubMed2003

Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis.

In response to changes in the external environment cells must initiate a coordinated program of gene expression for them to adapt. IEX-1 (immediate early response gene X-1) is precisely regulated by multiple transcription factors among which p53, NF-kappaB/rel, Sp1 and c-Myc play central roles, to ensure rapid and transient expression of IEX-1 in cells under a variety of stress conditions. Overexpression of IEX-1 renders some cells sensitive to apoptosis and accelerates cell cycle progression, but reduces proliferation of other cells, whereas disruption of IEX-1 expression is associated with decreases in both apoptosis and cell cycle progression. In sharp contrast to in vitro studies, in vivo constitutive expression of IEX-1 prevents activated T cells but not B cells from apoptosis, as shown using IEX-1-transgenic mice that target IEX-1 expression specifically to lymphocytes driven by the Emu enhancer. The animals developed a lupus-like disease and subsequently a high incidence of T cell lymphomas when they aged, due to insufficient apoptosis of T cells. These varied effects of IEX-1 on cell death and cell cycle progression in a cell-context dependent fashion implicate that IEX-1 is involved in more than one signaling pathway, understanding of which will certainly improve our knowledge with respect to cancer biology, cell death and cell cycle regulation.

Animals↗
PubMed2005

Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death.

Histone deacetylase 4 (HDAC4) undergoes signal-dependent shuttling between the cytoplasm and nucleus, which is regulated in part by calcium/calmodulin-dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC4 intracellular trafficking is important in regulating neuronal cell death. HDAC4 is normally localized to the cytoplasm in brain tissue and cultured cerebellar granule neurons (CGNs). However, in response to low-potassium or excitotoxic glutamate conditions that induce neuronal cell death, HDAC4 rapidly translocates into the nucleus of cultured CGNs. Treatment with the neuronal survival factor BDNF suppresses HDAC4 nuclear translocation, whereas a proapoptotic CaMK inhibitor stimulates HDAC4 nuclear accumulation. Moreover, ectopic expression of nuclear-localized HDAC4 promotes neuronal apoptosis and represses the transcriptional activities of myocyte enhancer factor 2 and cAMP response element-binding protein, survival factors in neurons. In contrast, inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppresses neuronal cell death. Finally, an increase of nuclear HDAC4 in granule neurons is also observed in weaver mice, which harbor a mutation that promotes CGN apoptosis. Our data identify HDAC4 and its intracellular trafficking as key effectors of multiple pathways that regulate neuronal cell death.

Animals↗
PubMed1999

Bone morphogenetic proteins regulate interdigital cell death in the avian embryo.

The embryonic limb bud provides an excellent model for analyzing the mechanisms that regulate programmed cell death during development. At the time of digit formation in the developing autopod, the undifferentiated distal mesodermal cells may undergo or chondrogenic differentiation or apoptosis depending whether they are incorporated into the future digital rays or into the interdigital spaces. Both chondrogenesis or apoptosis are induced by local BMPS. However, whereas the chondrogenic-promoting activity of BMPs appears to be regulated through the BMPR-1b receptor, the mechanism by which the BMPs execute the death program remains unknown. The BMP proapoptotic activity requires the expression of members of the msx family of closely related homeobox-containing genes and is finally mediated by caspase activation, but the nature of the caspase(s) directly responsible for the cell death is also unknown. Finally, other growth factors present in the developing autopod at the stages of digit formation such as members of the FGF and TGF beta families modulate the ability of BMPs to induce cell death or chondrogenesis.

Animals↗
PubMedDate not supplied

[Aspects of cellular biology of the bacterial stationary phase: programmed cell death and regulation by guanosine tetraphosphate].

The paper discusses (1) programmed cell death, the phenomenon typical of the stationary phase of bacteria occurring under unfavorable conditions, (2) its pleiotropic regulation by guanosine tetraphosphate, and (3) the conception of "addiction module," a specific genetic system responsible for the cell choice between survival and death under unfavorable conditions. The shortcomings of the proposed interpretation of the problem at hand are considered and the necessity of their further investigation is substantiated.

Apoptosis↗
PubMed1995

Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family.

The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. Bcl-2 inaugurated a new category of oncogenes, regulators of cell death. The Bcl-2 gene was identified at the chromosomal breakpoint of t(14;18) bearing B cell lymphomas. Bcl-2 proved unique by blocking programmed cell death rather than promoting proliferation. In adults, Bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress Bcl-2 demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two unexpected pathologies resulting from cell death, polycystic kidney disease and hair hypopigmentation. The latter is a potential oxidant injury from the melanin biosynthetic pathway. A family of Bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with Bcl-2 and promotes cell death. The ratio of family members, such as Bcl-2/Bax, determines the survival or death of cells following an apoptotic stimulus.

Amino Acid Sequence↗
PubMed2003

Reactive oxygen species and hormonal control of cell death.

The accumulation of reactive oxygen species (ROS) is involved in regulating cell death. Pathogen- and ozone-induced processes have become important models for the study of cell death regulation by ROS. Hydrogen peroxide and superoxide have emerged as the two key ROS and recent studies have addressed their sources and control of their production. ROS signals interact directly or indirectly with several other signaling pathways, such as nitric oxide, and the stress hormones salicylic acid, jasmonic acid and ethylene. The interaction and balance of these pathways determines whether the cell lives or dies.

Cell Death↗
PubMed2000

Expression of a specific glycosyltransferase enzyme regulates T cell death mediated by galectin-1.

Galectin-1 induces apoptosis of immature thymocytes and activated T cells, suggesting that galectin-1 regulates cell death in the thymus during selection and in the periphery following an immune response. Although it is known that galectin-1 recognizes lactosamine (Gal-GlcNAc) as a minimal ligand, this disaccharide is ubiquitously expressed on a variety of cell surface glycoproteins. Thus, susceptibility to galectin-1 may be regulated by the presentation of lactosamine on specific oligosaccharide structures created by specific glycosyltransferase enzymes. The core 2 beta-1, 6-N-acetylglucosaminyltransferase (core 2 GnT) creates a branched structure on O-glycans that can be elongated to present multiple lactosamine sequences. In the thymus, the core 2 GnT is expressed in galectin-1-sensitive thymocyte subsets. In the periphery, an oligosaccharide epitope created by the core 2 GnT is expressed on galectin-1-sensitive activated T-cells. In this report, we demonstrate that expression of the core 2 GnT was necessary and sufficient for galectin-1-induced death of murine T cell lines. In addition, overexpression of the core 2 GnT in mice increased the susceptibility of double positive thymocytes to galectin-1. These data demonstrate that expression of a specific glycosyltransferase can control susceptibility to galectin-1, suggesting that developmentally regulated glycosyltransferase expression may be a mechanism to modulate cell death during T cell development and function.

Amino Sugars↗
PubMed2005

[Selective "death programs" or pleiotropic"life programs"? Looking for programmed cell death in the light of evolution].

"Nothing in biology makes sense except in the light of evolution", wrote Theodosius Dobzhansky, one of the founders of the Modern Synthesis that led to the unification of evolutionary theory and genetics in the midst of the 20th century. Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new, and somehow puzzling level of complexity has recently begun to emerge, suggesting i) that several different self destruction pathways may exist and operate in parallel in our cells, and ii) that molecular effectors of cell suicide might also perform other functions unrelated to cell death induction and crucial to cell survival, such as cell differentiation, metabolism, and the regulation of the cell cycle. These new findings, with important physiopathological and therapeutic implications, seem at odds with the paradigm of programmed cell death derived from the studies of Caenorhabditis elegans, which led to the concept of the existence of selective, bona fide death genes that emerged and became selected for their sole capacity to execute or repress cell death. In this review, I will argue that this new level of complexity might only make sense and be understood when considered in a broader evolutionary context than that of our phylogenetic divergence from C. elegans. A new view of the regulated cell death pathways emerges when one attempts to ask the question of when and how they may have become selected during a timeline of 4 billion years, at the level of ancestral single-celled organisms, including the bacteria. I will argue that there may be no such thing as a bona fide genetic cell death program. Rather, in the framework of a model that I have termed the "original sin" hypothesis, I have proposed the existence of an initial pleiotropy of the molecular tools involved in the control and execution of self-destruction--an ancestral involvement in both pro-life and pro-death activities. I will discuss how this hypothesis may be reconciled with the C. elegans paradigm of programmed cell death. Finally I will discuss how an ancestral level of pleiotropic functions of the molecular tools involved in the control of cell death, aging and genetic diversification might have favored their initial selection, their constant availability for de novo selection, and their progressive propagation in most--if not all--species during the course of evolution.

Aging↗
PubMed2003

Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells.

Reactive oxygen species (ROS) cause cell death and are associated with a variety of maladies, from trauma and infection to organ degeneration and cancer. Cells mount a complex response to oxidative damage that includes signaling from transmembrane receptors and intracellular kinases. We have analyzed the response to oxidative damage in human breast cancer cells expressing the Hpr6.6 (human membrane progesterone receptor) protein. Although Hpr6.6 is related to a putative progesterone-binding protein, Hpr6.6 is widely expressed in epithelial tissues and shares close homology with a budding yeast damage response protein called Dap1p (damage response protein related to membrane progesterone receptor). We report here that the Hpr6.6 protein regulates the response to oxidative damage in breast cancer cells. Expression of Hpr6.6 in MCF-7 cells sensitized the cells to death following long-term/low dose or short-term/high dose treatment with hydrogen peroxide. Cell death did not occur through a typical apoptotic mechanism and corresponded with hyperphosphorylation of the Akt and IkappaB proteins. However, inhibition of Akt activation and IkappaB degradation had no effect on Hpr6.6-mediated cell death, suggesting that Hpr6.6 regulates cell death through a novel oxidative damage response pathway. Our work indicates a key regulatory function for Hpr6.6 in epithelial tissues exposed to oxidative damage.

Amino Acid Sequence↗
PubMed2002

Identification of X-linked genes required for migration and programmed cell death of Drosophila melanogaster germ cells.

Drosophila germ cells form at the posterior pole of the embryo and migrate to the somatic gonad. Approximately 50% of the germ cells that form reach their target. The errant cells within the embryo undergo developmentally regulated cell death. Prior studies have identified some autosomal genes that regulate germ cell migration, but the genes that control germ cell death are not known. To identify X-linked genes required for germ cell migration and/or death, we performed a screen for mutations that disrupt these processes. Here we report the identification of scattershot and outsiders, two genes that regulate the programmed death of germ cells. The scattershot gene is defined by a mutation that disrupts both germ cell migration and the death of germ cells ectopic to the gonad. Maternal and zygotic expression of scattershot is required, but the migration and cell death functions can be genetically uncoupled. Zygotic expression of wild-type scattershot rescues germ cell pathfinding, but does not restore the programmed death of errant cells. The outsiders gene is required zygotically. In outsiders mutant embryos, the appropriate number of germ cells is incorporated into the gonad, but germ cells ectopic to the gonad persist.

Animals↗
PubMed2002

Up-regulation of Hrk, a regulator of cell death, in retinal ganglion cells of axotomized rat retina.

Hrk, a regulator of cell death, belongs to the family of pro-apoptotic BH3-only proteins and is known to induce apoptosis in nerve tissue. We examined Hrk gene expression to clarify the role of BH3-only proteins in apoptosis of retinal ganglion cells (RGCs) after optic nerve transection in the adult rat. Reverse transcription-polymerase chain reaction showed that Hrk was up-regulated in retina from 12 h after axotomy, and continued to be elevated for 1 week. In situ hybridization histochemistry revealed that Hrk was expressed in a sub-population of axotomized RGCs. These results suggest that Hrk is involved in the induction of apoptosis in RGCs after optic nerve transection.

Animals↗