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      Unfertilized Xenopus Eggs Die by Bad-Dependent Apoptosis under the Control of Cdk1 and JNK

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          Abstract

          Ovulated eggs possess maternal apoptotic execution machinery that is inhibited for a limited time. The fertilized eggs switch off this time bomb whereas aged unfertilized eggs and parthenogenetically activated eggs fail to stop the timer and die. To investigate the nature of the molecular clock that triggers the egg decision of committing suicide, we introduce here Xenopus eggs as an in vivo system for studying the death of unfertilized eggs. We report that after ovulation, a number of eggs remains in the female body where they die by apoptosis. Similarly, ovulated unfertilized eggs recovered in the external medium die within 72 h. We showed that the death process depends on both cytochrome c release and caspase activation. The apoptotic machinery is turned on during meiotic maturation, before fertilization. The death pathway is independent of ERK but relies on activating Bad phosphorylation through the control of both kinases Cdk1 and JNK. In conclusion, the default fate of an unfertilized Xenopus egg is to die by a mitochondrial dependent apoptosis activated during meiotic maturation.

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          Identification of a novel inhibitor of mitogen-activated protein kinase kinase.

          The compound U0126 (1,4-diamino-2,3-dicyano-1, 4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but did not affect genes lacking an AP-1 response element in their promoters. These effects of U0126 result from direct inhibition of the mitogen-activated protein kinase kinase family members, MEK-1 and MEK-2. Inhibition is selective for MEK-1 and -2, as U0126 shows little, if any, effect on the kinase activities of protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2, or Cdk4. Comparative kinetic analysis of U0126 and the MEK inhibitor PD098059 (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci U. S. A. 92, 7686-7689) demonstrates that U0126 and PD098059 are noncompetitive inhibitors with respect to both MEK substrates, ATP and ERK. We further demonstrate that the two compounds bind to deltaN3-S218E/S222D MEK in a mutually exclusive fashion, suggesting that they may share a common or overlapping binding site(s). Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for deltaN3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the deltaN3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.
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            Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)

            Extracellular survival factors alter a cell's susceptibility to apoptosis, often through posttranslational mechanisms. However, no consistent relationship has been established between such survival signals and the BCL-2 family, where the balance of death agonists versus antagonists determines susceptibility. One distant member, BAD, heterodimerizes with BCL-X(L) or BCL-2, neutralizing their protective effect and promoting cell death. In the presence of survival factor IL-3, cells phosphorylated BAD on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated BAD heterodimerized with BCL-X(L) at membrane sites to promote cell death. Phosphorylated BAD was sequestered in the cytosol bound to 14-3-3. Substitution of serine phosphorylation sites further enhanced BAD's death-promoting activity. The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis.
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              Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.

              Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                16 August 2011
                : 6
                : 8
                : e23672
                Affiliations
                [1 ]CNRS, UMR 7622-Biologie du Développement, Paris, France
                [2 ]Université Pierre et Marie Curie-Paris 6, UMR 7622-Biologie du Développement, Paris, France
                Ecole Normale Supérieure de Lyon, France
                Author notes

                Conceived and designed the experiments: DDD CJ. Performed the experiments: DDP CJ. Analyzed the data: DDP AD CJ. Contributed reagents/materials/analysis tools: DDP CJ. Wrote the paper: DDP AD CJ.

                [¤]

                Current address: WatchFrog, Evry, France

                Article
                PONE-D-11-09829
                10.1371/journal.pone.0023672
                3156807
                21858202
                8132ce6e-b308-49a9-a075-b9a6510e15f4
                Du Pasquier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 June 2011
                : 22 July 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Developmental Biology
                Molecular Development
                Signaling
                Evolutionary Developmental Biology
                Fertilization
                Model Organisms
                Animal Models
                Xenopus Laevis
                Molecular Cell Biology
                Cell Division
                Cyclins
                Meiosis
                Cellular Types
                Germ Cells
                Signal Transduction
                Signaling Cascades
                Apoptotic Signaling Cascade
                Protein Kinase Signaling Cascade
                c-Jun N-terminal kinase signaling cascade
                Signaling in Cellular Processes
                Antiapoptotic Signaling
                Apoptotic Signaling
                Mitotic Signaling
                Signaling in Selected Disciplines
                Developmental Signaling
                Mechanisms of Signal Transduction
                Cell Death
                Zoology
                Animal Physiology

                Uncategorized
                Uncategorized

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