The Apoptosome: Physiological, Developmental, and Pathological Modes of Regulation

Schafer, Zachary T.; Kornbluth, Sally

doi:10.1016/j.devcel.2006.04.008

Cited by 215 publications

(188 citation statements)

References 140 publications

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“…9). Caspase 9 is control relatively to healthy (asterisk) and apoptotic cells dependent on the mitochondrial pathway for apoptosis (Garrido et al 2006;Schafer and Kornbluth 2006), confirming that mitochondria are involved in Doxinduced toxicity on H9c2 myoblasts. In fact, both mitochondrial-dependent (Ueno et al 2006) and mitochondrial-independent (Jang et al 2004) pathways have been described as involved in in vivo apoptosis induced by Dox in cardiac cells.…”

Section: Discussionmentioning

confidence: 74%

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

et al. 2008

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Doxorubicin (Dox) is a very potent antineoplastic agent used against several types of cancer, despite a cumulative cardiomyopathy that reduces the therapeutic index for treatment. H9c2 myoblast cells have been used as an in vitro model to study biochemical alterations induced by Dox treatment on cardiomyocyte cells. Despite the extensive work already published, few data are available regarding morphological alterations of H9c2 cells during Dox treatment. The purpose of the present work was to evaluate Doxinduced morphological alterations in H9c2 myoblasts, focusing especially on the nuclei, mitochondria, and structural fibrous proteins. Treatment of H9c2 cell with low concentrations of Dox causes alterations in fibrous structural proteins including the nuclear lamina and sarcomeric cardiac myosin, as well as mitochondrial depolarization and fragmentation, membrane blebbing with cell shape changes, and phosphatidylserine externalization. For higher Dox concentrations, more profound alterations are evident, including nuclear swelling with disruption of nuclear membrane structure, mitochondrial swelling, and extensive cytoplasm vacuolization. The results obtained indicate that Dox causes morphological alterations in mitochondrial, nuclear, and fibrous protein structures in H9c2 cells, which are dependent on the drug concentration. Data obtained with the present study allow for a better characterization of the effects of Dox on H9c2 myoblasts, used as a model to study Dox-induced cardiotoxicity. The results obtained also provide new and previously unknown targets that can contribute to understand the mechanisms involved in the cardiotoxicity of Dox.

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Section: Discussionmentioning

confidence: 74%

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

et al. 2008

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“…Indeed, Apaf1 has been reported to be a potent tumour suppressor and drug resistance inducer. 43 Therefore, the identification of factors modulating Apaf1 expression, such as Ku itself, The construct pCMV-pGL3-basic was generated cloning the CMV promoter upstream the luciferase cDNA into the BglII-SpeI sites.…”

Section: Discussionmentioning

confidence: 99%

The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage

et al. 2010

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Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, as it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and downregulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a downregulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 upregulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival.

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“…Furthermore, activation of the mitogen-activated protein kinase(3/6)-p38 signaling pathway in mammalian cells stressed by osmotic shock or UVC irradiation results in phosphorylation-dependent cytoplasmic accumulation of hnRNP A1 (van der Houven van Oordt et al, 2000;Allemand et al, 2005). Interestingly, UVC-dependent IRES-mediated translational control has recently been demonstrated for the apoptotic peptidase activating factor 1 (apaf-1) mRNA (Ungureanu et al, 2006), which encodes a proapoptotic protein involved in the formation of the apoptosome (Schafer and Kornbluth, 2006).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Relocalization of Heterogeneous Nuclear Ribonucleoprotein A1 Controls Translation Initiation of Specific mRNAs

Cammas

Pileur

Bonnal

et al. 2007

MBoC

136

130

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Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is a nucleocytoplasmic shuttling protein that regulates gene expression through its action on mRNA metabolism and translation. The cytoplasmic redistribution of hnRNP A1 is a regulated process during viral infection and cellular stress. Here, we show that hnRNP A1 is an internal ribosome entry site (IRES) trans-acting factor that binds specifically to the 5 untranslated region of both the human rhinovirus-2 and the human apoptotic peptidase activating factor 1 (apaf-1) mRNAs, thereby regulating their translation. Furthermore, the cytoplasmic redistribution of hnRNP A1 after rhinovirus infection leads to enhanced rhinovirus IRES-mediated translation, whereas the cytoplasmic relocalization of hnRNP A1 after UVC irradiation limits the UVC-triggered translational activation of the apaf-1 IRES. Therefore, this study provides a direct demonstration that IRESs behave as translational enhancer elements regulated by specific trans-acting mRNA binding proteins in given physiological conditions. Our data highlight a new way to regulate protein synthesis in eukaryotes through the subcellular relocalization of a nuclear mRNA-binding protein.

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The Apoptosome: Physiological, Developmental, and Pathological Modes of Regulation

Cited by 215 publications

References 140 publications

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage

Cytoplasmic Relocalization of Heterogeneous Nuclear Ribonucleoprotein A1 Controls Translation Initiation of Specific mRNAs

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