Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1.

Coordination and balance between cell survival and apoptosis is crucial for normal development and homeostasis of multicellular organisms. Defects in control of this balance may contribute to a variety of diseases including cancer, autoimmune and neurodegenerative conditions. Although a large number of pro- and anti-apoptotic factors acting for or against the final death event have been and are being discovered at an extraordinary pace with the recent progress in this area, the molecular mechanisms determining whether a cell lives or dies are not fully understood. Phosphorylation and dephosphorylation of intracellular effector molecules are the most common and important regulatory mechanisms in signal transduction and control a variety of cellular events from cell growth to apoptosis. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase kinase kinase family, which activates both the SEK1-JNK and MKK3/6-p38 MAP kinase pathways and constitutes a pivotal signaling pathway in cytokine- and stress-induced apoptosis. This review provides recent findings on the molecular mechanisms which determine cell fate such as survival, proliferation, differentiation or apoptosis, with special focus on the regulatory mechanisms of ASK1-mediated apoptosis.     

Proliferation and apoptosis in early molar morphogenesis-- voles as models in odontogenesis

Proliferation and apoptosis play crucial roles in the development of multicellular organisms. Their precise balance is necessary for tissue homeostasis throughout life. The developing dentition is a suitable model to study proliferation and apoptosis during embryogenesis, but the corresponding studies have been carried out principally in the mouse. The present study aimed to examine proliferation and apoptosis in the vole (Microtus sp., Rodentia) during the early morphogenesis of the first upper molar and compare it to what is known from the mouse. To this end, apoptosis and proliferation were investigated using histology and computer-aided 3D reconstruction. Mitoses accumulated predominantly in the developing cervical loop. Apoptosis during early odontogenesis showed highly specific spatio-temporal patterns in the dental epithelium. Apoptotic bodies were localised in non-dividing cell populations. They accumulated in the same places as described in the mouse: antemolar vestiges (ED 12.5 15.5), enamel knot (ED 14.5 15.5), stalk and palatally along the whole first molar tooth germ longitudinal axis (ED 15 - 15.5). Early tooth development in the field vole, including the distribution of apoptosis and mitosis, is very similar to that reported in the mouse, with the exception of the antemolar region. The microtine antemolar vestige is preserved longer than the murine one. It is conceivable that additional distinct differences in morphogenetic processes appear later in tooth development.     

Apoptosis and liver diseases

Regulation of homeostasic balance between cell proliferation and cell death, called apoptosis, is essential for development and maintenance of multicellular organisms. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically and evolutionarily conserved process that can become deranged when the components of the cellular apoptotic machinery are mutated, perturbated by viral gene products or present in inappropriated quantities. Analysis of the regulatory apoptotic pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases or autoimmune diseases. Our understanding of the regulation of apoptosis in health and disease is far from complete and the use of understanding into new therapeutic modalities has only begun to be approached.     

Role of Bcl-2 family proteins and caspases in the regulation of apoptosis

Apoptosis, or programmed cell death, plays a pivotal role in the elimination of unwanted, damaged, or infected cells in multicellular organisms and also in diverse biological processes, including development, cell differentiation, and proliferation. Apoptosis is a highly regulated form of cell death, and dysregulation of apoptosis results in pathological conditions including cancer, autoimmune and neurodegenerative diseases. The Bcl-2 family proteins are key regulators of apoptosis, which include both anti- and pro-apoptotic proteins, and a slight change in the dynamic balance of these proteins may result either in inhibition or promotion of cell death. Execution of apoptosis by various stimuli is initiated by activating either intrinsic or extrinsic pathways which lead to a series of downstream cascade of events, releasing of various apoptotic mediators from mitochondria and activation of caspases, important for the cell fate. In view of recent research advances about underlying mechanism of apoptosis, this review highlights the basics concept of apoptosis and its regulation by Bcl-2 family of protein. Furthermore, this review discusses the interplay of various apoptotic mediators and caspases to decide the fate of the cell. We expect that this review will add to the pool of basic information necessary to understand the mechanism of apoptosis which may implicate in designing better strategy to develop biomedical therapy to control apoptosis.     

Mitochondria: regulating the inevitable

Apoptosis is a form of programmed cell death important in the development and tissue homeostasis of multicellular organisms. Abnormalities in cell death control can lead to a variety of diseases, including cancer and degenerative disorders. Hence, the process of apoptosis is tightly regulated through multiple independent signalling pathways that are initiated either from triggering events within the cell or at the cell surface. In recent years, mitochondria have emerged as the central components of such apoptotic signalling pathways and are now known to control apoptosis through the release of apoptogenic proteins. In this review we aim to give an overview of the role of the mitochondria during apoptosis and the molecular mechanisms involved.     

Different cell cycle modifications repress apoptosis at different steps independent of developmental signaling in Drosophila

Apoptotic cell death is important for the normal development of a variety of organisms. Apoptosis is also a response to DNA damage and an important barrier to oncogenesis. The apoptotic response to DNA damage is dampened in specific cell types during development. Developmental signaling pathways can repress apoptosis, and reduced cell proliferation also correlates with a lower apoptotic response. However, because developmental signaling regulates both cell proliferation and apoptosis, the relative contribution of cell division to the apoptotic response has been hard to discern in vivo. Here we use Drosophila oogenesis as an in vivo model system to determine the extent to which cell proliferation influences the apoptotic response to DNA damage. We find that different types of cell cycle modifications are sufficient to repress the apoptotic response to ionizing radiation independent of developmental signaling. The step(s) at which the apoptosis pathway was repressed depended on the type of cell cycle modification—either upstream or downstream of expression of the p53-regulated proapoptotic genes. Our findings have important implications for understanding the coordination of cell proliferation with the apoptotic response in development and disease, including cancer and the tissue-specific responses to radiation therapy.     

昆虫卵子发生过程中细胞凋亡的研究进展

细胞凋亡是动物发育过程中的基本生命现象,是多细胞生物体一种重要的自我稳定机制。除体细胞发生凋亡外,生殖细胞在其发生过程中也有细胞凋亡。对近10年来昆虫卵子发生过程中细胞凋亡的研究作了综述。重点关注昆虫卵子发生过程中细胞凋亡发生的阶段、凋亡的形态特征、凋亡的调控及意义等,以期为相关研究提供基础资料。     

Ecological developmental biology: environmental signals for normal animal development

The environment plays instructive roles in development and selective roles in evolution. This essay reviews several of the instructive roles whereby the organism has evolved to receive cues from the environment in order to modulate its developmental trajectory. The environmental cues can be abiotic (such as temperature or photoperiod) or biotic (such as those emanating from predators, conspecifics, or food), and the “alteration” produces a normal, not a pathological, phenotype, that is appropriate for the environment. In addition, symbiotic organisms can produce important signals during normal development. Environmental cues can be obligatory, such that the organism cannot develop without the environmental cue. These cues often permit and instruct the organism to proceed from one developmental stage to another, as when larvae receive cues to settle and undergo metamorphosis from substrates. Such obligatory cues can also be given by symbionts, as when Wolbachia bacteria prevent apoptosis in developing ovaries of some wasps. Other environmental cues can be used facultatively, allowing organisms to follow different developmental trajectories depending on whether the cue is present or not. This can be seen in the temperature‐dependent determination of sex in many reptiles and in the determination of thermotolerance in aphids by their symbiotic bacteria. Signaling from the environment is essential in development, and co‐development appears to be normative between symbionts and their hosts. Here, one sees the reciprocal induction of gene expression, just as within the embryonic organism. The ability of organisms to respond to environmental cues by producing different phenotypes may be critically important in evolution, and it may be an essential feature that can facilitate or limit evolution.     

Death penalty for keratinocytes: apoptosis versus cornification

Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.     

Apoptosis: why and how does it occur in biology?

The literature on apoptosis has grown tremendously in recent years, and the mechanisms that are involved in this programmed cell death pathway have been enlightened. It is now known that apoptosis takes place starting from early development to adult stage for the homeostasis of multicellular organisms, during disease development and in response to different stimuli in many different systems. In this review, we attempted to summarize the current knowledge on the circumstances and the mechanisms that lead to induction of apoptosis, while going over the molecular details of the modulator and mediators of apoptosis as well as drawing the lines between programmed and non-programmed cell death pathways. The review will particularly focus on Bcl-2 family proteins, the role of different caspases in the process of apoptosis, and their inhibitors as well as the importance of apoptosis during different disease states. Understanding the molecular mechanisms involved in apoptosis better will make a big impact on human diseases, particularly cancer, and its management in the clinics.     

Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila

Programmed cell death or apoptosis plays an important role in the development of multicellular organisms and can also be induced by various stress events. In the Drosophila wing imaginal disc there is little apoptosis in normal development but X-rays can induce high apoptotic levels, which eliminate a large fraction of the disc cells. Nevertheless, irradiated discs form adult patterns of normal size, indicating the existence of compensatory mechanisms. We have characterised the apoptotic response of the wing disc to X-rays and heat shock and also the developmental consequences of compromising apoptosis. We have used the caspase inhibitor P35 to prevent the death of apoptotic cells and found that it causes increased non-autonomous cell proliferation, invasion of compartments and persistent misexpression of the wingless (wg) and decapentaplegic (dpp) signalling genes. We propose that a feature of cells undergoing apoptosis is to activate wg and dpp, probably as part of the mechanism to compensate for cell loss. If apoptotic cells are not eliminated, they continuously emit Wg and Dpp signals, which results in developmental aberrations. We suggest that a similar process of uncoupling apoptosis initiation and cell death may occur during tumour formation in mammalian cells.     

Bcl-2 family members and disease

Apoptosis plays an important role during development and in the maintenance of multicellular organisms. Bcl-2 family members affect cell death in either a positive or negative fashion. Although some redundancy exists between family members, expression of certain family members is important during development in an organ-specific manner. The founding family member bcl-2 tends to be highly expressed in the embryo and declines postnatally following differentiation and maturation. Altered expression of bcl-2, as well as other family members, has been observed in disease states potentially affecting treatment modalities. Here we examine the distribution and role death repressors bcl-2, bcl-x(L) and bcl-w as well as death effectors bax and bak play regulating apoptosis in a tissue-specific manner. Understanding the normal role of these proteins during embryogenesis and in the mature organ will give us important insight into what goes awry in various disease states.     

Plant programmed cell death: can't live with it; can't live without it

The decision of whether a cell should live or die is fundamental for the wellbeing of all organisms. Despite intense investigation into cell growth and proliferation, only recently has the essential and equally important idea that cells control/programme their own demise for proper maintenance of cellular homeostasis gained recognition. Furthermore, even though research into programmed cell death (PCD) has been an extremely active area of research there are significant gaps in our understanding of the process in plants. In this review, we discuss PCD during plant development and pathogenesis, and compare/contrast this with mammalian apoptosis.     

The shadow of death on the MET tyrosine kinase receptor

The MET tyrosine kinase receptor is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-MET system is necessary for embryonic development, and aberrant MET signalling favours tumorigenesis and metastasis. MET is a prototype of tyrosine kinase receptor, which is able to counteract apoptosis through the initiation of a survival signal involving notably the PI3K-Akt pathway. Paradoxically, the MET receptor is also able to promote apoptosis when activated by HGF/SF or independently of ligand stimulation. The molecular mechanisms underlying this uncommon response have been recently investigated and revealed dual antiapoptotic or proapoptotic property of MET according to the cell type or stress conditions. Although the involvement of MET in the regulation of integrated biological responses mostly took into account its efficient antiapoptotic function, its proapoptotic responses could also be important for regulation of the survival/apoptosis balance and play a role during the development or tumour progression.     

The Bcl-2 family in autoimmune and degenerative disorders

Members of the Bcl-2 family are essential regulators of programmed cell death and thus play a major role in the development and function of many tissues. The balance between pro-survival and pro-apoptotic members of the family decides whether a cell will live or die. This mechanism allows organisms to get rid of cells that are no longer needed or have become dangerous. Deregulation of apoptosis is a major contributing factor in the development of many diseases. A deeper understanding of how the Bcl-2 family proteins orchestrate death in normal and pathologic conditions is thus relevant not only for disease etiology, but also to try to prevent these various disorders. Experiments with transgenic and gene-ablated mice have helped elucidate the function of the different members of the Bcl-2 family and their physiological roles. The present review highlights the role of Bcl-2 family members in autoimmune and degenerative disorders, with a particular focus on the mouse models that have been used to study their function.     

细胞凋亡与细胞程序性死亡

细胞凋亡与程序性死亡是多细胞动物生命过程中必不可少的正常过程,它与细胞增殖具有同样重要意义。细胞凋亡与程序性死亡失控不仅扰乱发育,还导致病变。因此,这一领域的研究受到生命科学研究者的广泛重视,进展很快。本文从凋亡的定义、形态学特点、诱导、生物化学背景、基因调控等５个方面综合分析了近年来国内外的研究进展。     

Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis

MAPK phosphatases (MKPs) are important negative regulators of MAPKs in vivo, but ascertaining the role of specific MKPs is hindered by functional redundancy in vertebrates. Thus, we characterized MKP function by examining the function of Puckered (Puc), the sole Drosophila Jun N-terminal kinase (JNK)-specific MKP, during embryonic and imaginal disc development. We demonstrate that Puc is a key anti-apoptotic factor that prevents apoptosis in epithelial cells by restraining basal JNK signaling. Furthermore, we demonstrate that JNK signaling plays an important role in gamma-irradiation-induced apoptosis, and examine how JNK signaling fits into the circuitry regulating this process. Radiation upregulates both JNK activity and puc expression in a p53-dependent manner, and apoptosis induced by loss of Puc can be suppressed by p53 inactivation. JNK signaling acts upstream of both Reaper and effector caspases. Finally, we demonstrate that JNK signaling directs normal developmentally regulated apoptotic events. However, if cell death is prevented, JNK activation can trigger tissue overgrowth. Thus, MKPs are key regulators of the delicate balance between proliferation, differentiation and apoptosis during development.     

Ecological Developmental Biology: Interpreting Developmental Signs

Developmental biology is a theory of interpretation. Developmental signals are interpreted differently depending on the previous history of the responding cell. Thus, there is a context for the reception of a signal. While this conclusion is obvious during metamorphosis, when a single hormone instructs some cells to proliferate, some cells to differentiate, and other cells to die, it is commonplace during normal development. Paracrine factors such as BMP4 can induce apoptosis, proliferation, or differentiation depending upon the history of the responding cells. In addition, organisms have evolved to alter their development in response to differences in temperature, diet, the presence of predators, or the presence of competitors. This allows them to develop the phenotype, within the limits imposed by the genotype, best suited for the immediate habitat of the organism. Most developing organisms have also evolved to expect developmental signals from symbionts, and these organisms develop abnormally if the symbiont signals are not present. Thus Hoffmeyer’s “vertical semiotic system” of genetic communication and “horizontal semiotic system” of ecological communication are integrated during development.     

Cell death mechanisms: Cross-talk and role in disease

Multiple cell death mechanisms operate in both uni- and multicellular organisms. Hence, research during the past forty years has revealed that apoptosis is not the only cell death program involved in the regulation of tissue homeostasis and the removal of unwanted cells in biological organisms. While the molecular pathways of apoptosis and necrosis are now relatively well established, the precise mechanisms of other cell death modalities, and their cross-talk, require additional study. This is particularly important, since many human disorders can be attributed, directly or indirectly, to defective cell death mechanisms. In this review we shall discuss the characteristics and cross-talk between various modes of cell death and their role in cell death-related disorders, notably, neurodegenerative disease and cancer.