Caspase 的活化机制

Caspase是一类与凋亡密切相关的蛋白水解酶家族,以Caspase前体酶原的形式存在大多后生动物的细胞中。Caspase在凋亡信号的作用下首先激活启动型Caspase引发Caspase级联反应,然后通过活化的执行型Caspase裂解特异性底物导致细胞凋亡。Caspase的活化是导致细胞凋亡的中心环节,位于Caspase级联反应上游的启动型Caspase的和下游的执行型Caspase有着明显不同的活化机制。     

Caspase激活与调控的分子机制

Caspases是一类天冬氨酸特异性的半胱氨酸蛋白酶(IL-1β转化酶相关蛋白酶).迄今,在哺乳动物至少已发现13种caspase成员.Caspases在胞内通常以无活性的酶原形式存在,在其内部特定的天冬氨酸残基部位蛋白质裂解加工后可导致酶原激活,引发细胞凋亡.作为效应子的caspase在绝大多数细胞的凋亡过程中具有十分重要的作用.随着线虫死亡程序及某些死亡受体介导敏感细胞凋亡的信号机制的阐明,人们对caspase激活与调控在细胞凋亡中的机制研究已获得重大进展.     

Cellular Mechanisms of Entrainment

This review summarizes our current understanding of the signal transduction cascade by which light causes phase shifts of the circadian oscillators found in the eye of Bulla and Aplysia. The isolated retina of these marine mollusks contains a circadian oscillator, a photoreceptor, and a light transduction pathway sufficient for entrainment. This preparation offers unique advantages for the cellular analysis of entrainment and the generation of circadian oscillations. There is evidence that similar cellular mechanisms may underlie mammalian and molluskan circadian oscillations. Thus, the models developed to explain entrainment in the molluskan retina are likely to have utility in exploring the mammalian supra-chiasmatic nucleus.     

Cellular Mechanisms of Entrainment

This review summarizes our current understanding of the signal transduction cascade by which light causes phase shifts of the circadian oscillators found in the eye of Bulla and Aplysia. The isolated retina of these marine mollusks contains a circadian oscillator, a photoreceptor, and a light transduction pathway sufficient for entrainment. This preparation offers unique advantages for the cellular analysis of entrainment and the generation of circadian oscillations. There is evidence that similar cellular mechanisms may underlie mammalian and molluskan circadian oscillations. Thus, the models developed to explain entrainment in the molluskan retina are likely to have utility in exploring the mammalian supra-chiasmatic nucleus.     

Cellular Mechanisms Regulating Adrenocorticotropin Release

Abstract

Using a tumor cell line of the mouse anterior pituitary (AtT-20/D16-16), the various factors regulating ACTH release and the intracellular mechanisms mediating this response were investigated. CRF, catechola-mines and VIP stimulate ACTH release whereas glucocorticoids and SRIF block secretion. Glucocorticoids block both ACTH synthesis and release. SRIF acts through multiple mechanisms to prevent stimulated ACTH release. Cyclic AMP and Ca⁺⁺ are important second messengers in the receptor mediated release of ACTH but other mediators may also be involved. The interaction of these various CRF-like substances and inhibitors of ACTH release may result in a fine-tune regulation of corticotroph activity Such regulation may be important in the organism response to stress.     

Cellular Mechanisms of Interferon Production

Rabbit kidney cell cultures stimulated with either double-stranded polyinosinate-polycytidylate (poly I:poly C) or with ultraviolet-irradiated Newcastle disease virus (UV-NDV) produce two types of interferon response, designated "early" and "late," respectively. The early response is suppressed by inhibitors of RNA or protein synthesis and is therefore thought to represent de novo synthesis of interferon. Circumstantial evidence suggested that this interferon response is regulated by a translation control mechanism. Late interferon production with poly I:poly C only took place in the presence of inhibitors of RNA or protein synthesis. The late interferon is therefore likely to be derived by the activation of an interferon precursor. The stimulation of late poly I:poly C-induced interferon production by cycloheximide suggested the existence of a second, posttranslational level of control of interferon production. This posttranslation control seems to be activated by interferon. UV-NDV can probably suppress the synthesis of the posttranslation inhibitory protein, and therefore it stimulates a late interferon response in the absence of inhibitors of RNA or protein synthesis. It is postulated that both the translation and posttranslation inhibitor participate in the development of a cellular refractory state to repeated interferon stimulation. The picture of interferon which emerges from this study is one of a heterogenous class of proteins whose production is controlled by cellular repressors acting at various levels.     

Swainsonine Induces Apoptosis through Mitochondrial Pathway and Caspase Activation in Goat Trophoblasts

The indolizidine alkaloid swainsonine (SW) has been reported to impair placentae and ultimately cause abortion in pregnant goats. Up to now, however, the precise effects of SW on goat trophoblast cells (GTCs) are still unclear. In this study, the cytotoxicity effects of SW on GTCs were detected and evaluated by MTT assay, AO/EB double staining, DNA fragmentation assay and flow cytometry analysis. Results showed that SW treatment significantly suppressed GTCs viability and induced typical apoptotic features in a time- and concentration-dependent manner. SW treatment increased Bax protein levels, reduced Bcl-2 protein levels, induced Bax translocation to mitochondria, and triggered the release of cytochrome c from mitochondria into cytosol, which in turn activated caspase-9 and caspase-3, and cleaved PARP, resulting in GTCs apoptosis. However, caspase-8 activity and the level of Bid did not exhibit significant changes in the process of SW-induced apoptosis. In addition, TUNEL assay suggested that SW induced GTCs apoptosis but not other cells in goat placenta cotyledons. Taken together, these data suggest that SW selectively induces GTCs apoptosis via the activation of mitochondria-mediated apoptosis pathway in goat placenta cotyledons, which might contribute to placentae impairment and abortion in pregnant goats fed with SW-containing plants. These findings may provide new insights to understand the mechanisms involved in SW-caused goat''s abortion.     

Sublethal Caspase Activation Promotes Generation of Cardiomyocytes from Embryonic Stem Cells

Generation of new cardiomyocytes is critical for cardiac repair following myocardial injury, but which kind of stimuli is most important for cardiomyocyte regeneration is still unclear. Here we explore if apoptotic stimuli, manifested through caspase activation, influences cardiac progenitor up-regulation and cardiomyocyte differentiation. Using mouse embryonic stem cells as a cellular model, we show that sublethal activation of caspases increases the yield of cardiomyocytes while concurrently promoting the proliferation and differentiation of c-Kit⁺/α-actinin^low cardiac progenitor cells. A broad-spectrum caspase inhibitor blocked these effects. In addition, the caspase inhibitor reversed the mRNA expression of genes expressed in cardiomyocytes and their precursors. Our study demonstrates that sublethal caspase-activation has an important role in cardiomyocyte differentiation and may have significant implications for promoting cardiac regeneration after myocardial injury involving exogenous or endogenous cell sources.     

Caspase 2 Activation and ER Stress Drive Rapid Jurkat Cell Apoptosis by Clofibrate

Differently from the antiapoptotic action most commonly assigned to peroxisome proliferators (PPs), we demonstrated that some of them, clofibrate (CF) in particular, display clearcut apoptogenic properties on rat hepatoma cell lines. We and others could confirm that CF as well as various other PPs can induce apoptosis in a variety of cells, including human liver, breast and lung cancer cell lines. The present study was aimed at investigating the cytotoxic action of CF on a neoplastic line of different origin, the human T leukemia Jurkat cells. We observed that CF rapidly triggers an extensive and morphologically typical apoptotic process on Jurkat cells, though not in primary T cells, which is completely prevented by the polycaspase inhibitor zVADfmk. Gene silencing studies demonstrated that CF-induced apoptosis in Jurkat cells is partially dependent on activation of caspase 2. Looking for a possible trigger of caspase 2 activation, we observed increased levels of phosphorylated eIF2α and JNK in CF-treated cells. Moreover, intracellular Ca²⁺ homeostasis was perturbed. Together, these findings are suggestive for the occurrence of ER stress, an event that is known to have the potential to activate caspase 2. The present observations demonstrate that CF induces in Jurkat cells a very fast and extensive apoptosis, that involves induction of ER stress and activation of caspases 2 and 3. Since apoptosis in Jurkat cells occurs at pharmacologically relevant concentrations of CF, the present findings encourage further in depth analysis in order to work out the potential implications of CF cytotoxcity on leukemic cells.     

Decoding Cellular Mechanisms for Mechanosensory Discrimination

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Molecular Mechanisms of Cellular Cholesterol Efflux

Most types of cells in the body do not express the capability of catabolizing cholesterol, so cholesterol efflux is essential for homeostasis. For instance, macrophages possess four pathways for exporting free (unesterified) cholesterol to extracellular high density lipoprotein (HDL). The passive processes include simple diffusion via the aqueous phase and facilitated diffusion mediated by scavenger receptor class B, type 1 (SR-BI). Active pathways are mediated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, which are membrane lipid translocases. The efflux of cellular phospholipid and free cholesterol to apolipoprotein A-I promoted by ABCA1 is essential for HDL biogenesis. Current understanding of the molecular mechanisms involved in these four efflux pathways is presented in this minireview.     

Cellular prion protein activates Caspase 3 for apoptotic defense mechanism in astrocytes

Molecular and Cellular Biochemistry - The cellular prion protein (PrPC) is anchored in the plasma membrane of cells, and it is highly present in cells of brain tissue, exerting numerous cellular...