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187 results on '"Martinou, J-C"'

6. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate

Author

Sica V., Bravo-San Pedro J. M., Izzo V., Pol J., Pierredon S., Enot D., Durand S., Bossut N., Chery A., Souquere S., Pierron G., Vartholomaiou E., Zamzami N., Soussi T., Sauvat A., Mondragon L., Kepp O., Galluzzi L., Martinou J. -C., Hess-Stumpp H., Ziegelbauer K., Kroemer G., Maiuri M. C., Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Institut Gustave Roussy (IGR), University of Geneva [Switzerland], Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Cancer Center Karolinska [Karolinska Institutet] (CCK), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, Bayer Pharma AG [Berlin], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Gestionnaire, Hal Sorbonne Université, Université de Genève = University of Geneva (UNIGE), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Sica, V., Bravo-San Pedro, J. M., Izzo, V., Pol, J., Pierredon, S., Enot, D., Durand, S., Bossut, N., Chery, A., Souquere, S., Pierron, G., Vartholomaiou, E., Zamzami, N., Soussi, T., Sauvat, A., Mondragon, L., Kepp, O., Galluzzi, L., Martinou, J. -C., Hess-Stumpp, H., Ziegelbauer, K., Kroemer, G., and Maiuri, M. C.

Subjects
Glycolysi, parthanato, mitochondrial fragmentation, Poly (ADP-Ribose) Polymerase-1, Mice, Nude, cancer metabolism, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Oxadiazole, Oxidative Phosphorylation, Ketoglutaric Acid, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, MDM2, parthanatos, Cell Line, Tumor, Animals, Humans, RNA, Small Interfering, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, Oxadiazoles, Electron Transport Complex I, Animal, regulated cell death, Apoptosi, Apoptosis Inducing Factor, Proto-Oncogene Proteins c-mdm2, glycolysis, Isocitrate Dehydrogenase, Mitochondria, lcsh:Biology (General), Pyrazole, Ketoglutaric Acids, Pyrazoles, Female, RNA Interference, Tumor Suppressor Protein p53, Krebs cycle, Human
Abstract

Summary: Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens. : Sica et al. show that respiratory chain inhibition by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87) becomes lethal for cancer cells when glycolysis is simultaneously suppressed. When combined with B87, dimethyl α-ketoglutarate acquires the capacity to suppress glycolysis, thus lethally poisoning bioenergetics metabolism. This therapeutic combination effect relies on transcriptional reprogramming that can be reverted by pharmacological inhibition of MDM2. Keywords: MDM2, Krebs cycle, glycolysis, mitochondrial fragmentation, regulated cell death, parthanatos, cancer metabolism

Published
2019
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10. A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression

Author

Wilson, W. C., Hornig-Do, H.-T., Bruni, F., Chang, J. H., Jourdain, A. A., Martinou, J.-C., Falkenberg, M., Spahr, H., Larsson, N.-G., Lewis, R. J., Hewitt, L., Basle, A., Cross, H. E., Tong, L., Lebel, R. R., Crosby, A. H., Chrzanowska-Lightowlers, Z. M. A., and Lightowlers, R. N.

Subjects
RNA, Mitochondrial, Primary Cell Culture, Gene Expression, Polynucleotide Adenylyltransferase, RNA-Binding Proteins, Articles, Fibroblasts, Fibroblasts/metabolism, Humans, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Mutation, Neoplasm Proteins/metabolism, Oxidative Phosphorylation, Polynucleotide Adenylyltransferase/genetics, Polynucleotide Adenylyltransferase/metabolism, RNA Processing, Post-Transcriptional, RNA, Messenger/metabolism, RNA-Binding Proteins/metabolism, Neoplasm Proteins, Mitochondrial Proteins, RNA, Messenger
Abstract

The p.N478D missense mutation in human mitochondrial poly(A) polymerase (mtPAP) has previously been implicated in a form of spastic ataxia with optic atrophy. In this study, we have investigated fibroblast cell lines established from family members. The homozygous mutation resulted in the loss of polyadenylation of all mitochondrial transcripts assessed; however, oligoadenylation was retained. Interestingly, this had differential effects on transcript stability that were dependent on the particular species of transcript. These changes were accompanied by a severe loss of oxidative phosphorylation complexes I and IV, and perturbation of de novo mitochondrial protein synthesis. Decreases in transcript polyadenylation and in respiratory chain complexes were effectively rescued by overexpression of wild-type mtPAP. Both mutated and wild-type mtPAP localized to the mitochondrial RNA-processing granules thereby eliminating mislocalization as a cause of defective polyadenylation. In vitro polyadenylation assays revealed severely compromised activity by the mutated protein, which generated only short oligo(A) extensions on RNA substrates, irrespective of RNA secondary structure. The addition of LRPPRC/SLIRP, a mitochondrial RNA-binding complex, enhanced activity of the wild-type mtPAP resulting in increased overall tail length. The LRPPRC/SLIRP effect although present was less marked with mutated mtPAP, independent of RNA secondary structure. We conclude that (i) the polymerase activity of mtPAP can be modulated by the presence of LRPPRC/SLIRP, (ii) N478D mtPAP mutation decreases polymerase activity and (iii) the alteration in poly(A) length is sufficient to cause dysregulation of post-transcriptional expression and the pathogenic lack of respiratory chain complexes.

Published
2014

11. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, Kroemer, G, Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, and Kroemer, G

Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Published
2018

16. Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015

Author

Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., Calzavara Pinton, P., Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., and Calzavara Pinton, P.

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Published
2015

18. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Author

Galluzzi, L, primary, Bravo-San Pedro, J M, additional, Vitale, I, additional, Aaronson, S A, additional, Abrams, J M, additional, Adam, D, additional, Alnemri, E S, additional, Altucci, L, additional, Andrews, D, additional, Annicchiarico-Petruzzelli, M, additional, Baehrecke, E H, additional, Bazan, N G, additional, Bertrand, M J, additional, Bianchi, K, additional, Blagosklonny, M V, additional, Blomgren, K, additional, Borner, C, additional, Bredesen, D E, additional, Brenner, C, additional, Campanella, M, additional, Candi, E, additional, Cecconi, F, additional, Chan, F K, additional, Chandel, N S, additional, Cheng, E H, additional, Chipuk, J E, additional, Cidlowski, J A, additional, Ciechanover, A, additional, Dawson, T M, additional, Dawson, V L, additional, De Laurenzi, V, additional, De Maria, R, additional, Debatin, K-M, additional, Di Daniele, N, additional, Dixit, V M, additional, Dynlacht, B D, additional, El-Deiry, W S, additional, Fimia, G M, additional, Flavell, R A, additional, Fulda, S, additional, Garrido, C, additional, Gougeon, M-L, additional, Green, D R, additional, Gronemeyer, H, additional, Hajnoczky, G, additional, Hardwick, J M, additional, Hengartner, M O, additional, Ichijo, H, additional, Joseph, B, additional, Jost, P J, additional, Kaufmann, T, additional, Kepp, O, additional, Klionsky, D J, additional, Knight, R A, additional, Kumar, S, additional, Lemasters, J J, additional, Levine, B, additional, Linkermann, A, additional, Lipton, S A, additional, Lockshin, R A, additional, López-Otín, C, additional, Lugli, E, additional, Madeo, F, additional, Malorni, W, additional, Marine, J-C, additional, Martin, S J, additional, Martinou, J-C, additional, Medema, J P, additional, Meier, P, additional, Melino, S, additional, Mizushima, N, additional, Moll, U, additional, Muñoz-Pinedo, C, additional, Nuñez, G, additional, Oberst, A, additional, Panaretakis, T, additional, Penninger, J M, additional, Peter, M E, additional, Piacentini, M, additional, Pinton, P, additional, Prehn, J H, additional, Puthalakath, H, additional, Rabinovich, G A, additional, Ravichandran, K S, additional, Rizzuto, R, additional, Rodrigues, C M, additional, Rubinsztein, D C, additional, Rudel, T, additional, Shi, Y, additional, Simon, H-U, additional, Stockwell, B R, additional, Szabadkai, G, additional, Tait, S W, additional, Tang, H L, additional, Tavernarakis, N, additional, Tsujimoto, Y, additional, Vanden Berghe, T, additional, Vandenabeele, P, additional, Villunger, A, additional, Wagner, E F, additional, Walczak, H, additional, White, E, additional, Wood, W G, additional, Yuan, J, additional, Zakeri, Z, additional, Zhivotovsky, B, additional, Melino, G, additional, and Kroemer, G, additional

Published
2014
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20. TCTP protects from apoptotic cell death by antagonizing bax function

Author

Susini, L, primary, Besse, S, additional, Duflaut, D, additional, Lespagnol, A, additional, Beekman, C, additional, Fiucci, G, additional, Atkinson, A R, additional, Busso, D, additional, Poussin, P, additional, Marine, J-C, additional, Martinou, J-C, additional, Cavarelli, J, additional, Moras, D, additional, Amson, R, additional, and Telerman, A, additional

Published
2008
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38. Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes.

Author

Lucken-Ardjomande, S., Montessuit, S., and Martinou, J.-C.

Subjects
APOPTOSIS, CHOLESTEROL, LIPIDS, MITOCHONDRIAL membranes, LIPOSOMES
Abstract

Activation of Bax or Bak is essential for the completion of many apoptotic programmes. Under cytotoxic conditions, these proteins undergo a series of conformational rearrangements that end up with their oligomerization. We found that unlike inactive monomeric Bax, active oligomerized Bax is partially resistant to trypsin digestion, providing a convenient read out to monitor Bax activation. Using this assay, we studied how the lipid composition of membranes affects tBid-induced Bax activation in vitro with pure liposomes. We report that Bax activation is inhibited by cholesterol and by decreases in membrane fluidity. This observation was further tested in vivo using the drug U18666A, which we found increases mitochondrial cholesterol levels. When incubated with tBid, mitochondria isolated from U18666A-treated cells showed a delay in the release of Smac/Diablo and Cytochrome c, as well as in Bax oligomerization. Moreover, pre-incubation with U18666A partially protected cells from stress-induced apoptosis. As many tumours display high mitochondrial cholesterol content, inefficient Bax oligomerization might contribute to their resistance to apoptosis-inducing agents.Cell Death and Differentiation (2008) 15, 484–493; doi:10.1038/sj.cdd.4402280; published online 14 December 2007 [ABSTRACT FROM AUTHOR]

Published
2008
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44. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1.

Author

Maundrell, K, Antonsson, B, Magnenat, E, Camps, M, Muda, M, Chabert, C, Gillieron, C, Boschert, U, Vial-Knecht, E, Martinou, J C, and Arkinstall, S

Abstract

We have studied the phosphorylation of the Bcl-2 family of proteins by different mitogen-activated protein (MAP) kinases. Purified Bcl-2 was found to be phosphorylated by the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) p54-SAPKbeta, and this is specific insofar as the extracellular signal-regulated kinase 1 (ERK1) and p38/RK/CSBP (p38) catalyzed only weak modification. Bcl-2 undergoes similar phosphorylation in COS-7 when coexpressed together with p54-SAPKbeta and the constitutive Rac1 mutant G12V. This is seen by both 32PO4 labeling and the appearance of five discrete Bcl-2 bands with reduced gel mobility. As anticipated, both intracellular p54-SAPKbeta activation and Bcl-2 phosphorylation are blocked by co-transfection with the MAP kinase specific phosphatase MKP3/PYST1. MAP kinase specificity is also seen in COS-7 cells as Bcl-2 undergoes only weak phosphorylation when co-expressed with enzymatically activated ERK1 or p38. Four critical residues undergoing phosphorylation in COS-7 cells were identified by expression of the quadruple Bcl-2 point mutant T56A,S70A,T74A, S87A. Sequencing phosphopeptides derived from tryptic digests of Bcl-2 indicates that purified GST-p54-SAPKbeta phosphorylates identical sites in vitro. This is the first report of Bcl-2 phosphorylation by the JNK/SAPK class of MAP kinases and could indicate a key modification allowing control of Bcl-2 function by cell surface receptors, Rho family GTPases, and/or cellular stresses.

Published
1997

45. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase.

Author

Muda, M, Boschert, U, Dickinson, R, Martinou, J C, Martinou, I, Camps, M, Schlegel, W, and Arkinstall, S

Abstract

MKP-1 (also known as CL100, 3CH134, Erp, and hVH-1) exemplifies a class of dual-specificity phosphatase able to reverse the activation of mitogen-activated protein (MAP) kinase family members by dephosphorylating critical tyrosine and threonine residues. We now report the cloning of MKP-3, a novel protein phosphatase that also suppresses MAP kinase activation state. The deduced amino acid sequence of MKP-3 is 36% identical to MKP-1 and contains the characteristic extended active-site sequence motif VXVHCXXGXSRSXTXXXAYLM (where X is any amino acid) as well as two N-terminal CH2 domains displaying homology to the cell cycle regulator Cdc25 phosphatase. When expressed in COS-7 cells, MKP-3 blocks both the phosphorylation and enzymatic activation of ERK2 by mitogens. Northern analysis reveals a single mRNA species of 2.7 kilobases with an expression pattern distinct from other dual-specificity phosphatases. MKP-3 is expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis. In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus. Metrazole-stimulated seizure activity triggers rapid (<1 h) but transient up-regulation of MKP-3 mRNA in the cortex, piriform cortex, and some amygdala nuclei. Metrazole stimulated similar regional up-regulation of MKP-1, although this was additionally induced within the thalamus. MKP-3 mRNA also undergoes powerful induction in PC12 cells after 3 h of nerve growth factor treatment. This response appears specific insofar as epidermal growth factor and dibutyryl cyclic AMP fail to induce significant MKP-3 expression. Subcellular localization of epitope-tagged MKP-3 in sympathetic neurons reveals expression in the cytosol with exclusion from the nucleus. Together, these observations indicate that MKP-3 is a novel dual-specificity phosphatase that displays a distinct tissue distribution, subcellular localization, and regulated expression, suggesting a unique function in controlling MAP kinase family members. Identification of a second partial cDNA clone (MKP-X) encoding the C-terminal 280 amino acids of an additional phosphatase that is 76% identical to MKP-3 suggests the existence of a distinct structurally homologous subfamily of MAP kinase phosphatases.

Published
1996

48. The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules

Author

Zaganelli, S, Rebelo-Guiomar, P, Maundrell, K, Rozanska, A, Pierredon, S, Powell, CA, Jourdain, AA, Hulo, N, Lightowlers, RN, Chrzanowska-Lightowlers, ZM, Minczuk, M, and Martinou, J-C

Subjects
mitochondria, ribosome, RNA-binding protein, mitoribosome biogenesis, RNA, RPUSD, RNA modification, OXPHOS, pseudouridine, 3. Good health
Abstract

Mitochondrial gene expression is a fundamental process that is largely dependent on nuclear-encoded proteins. Several steps of mitochondrial RNA processing and maturation, including RNA post-transcriptional modification, appear to be spatially organized into distinct foci, which we have previously termed mitochondrial RNA granules (MRGs). Although an increasing number of proteins have been localized to MRGs, a comprehensive analysis of the proteome of these structures is still lacking. Here, we have applied a microscopy-based approach that has allowed us to identify novel components of the MRG proteome. Among these, we have focused our attention on RPUSD4, an uncharacterized mitochondrial putative pseudouridine synthase. We show that RPUSD4 depletion leads to a severe reduction of the steady-state level of the 16S mitochondrial (mt) rRNA with defects in the biogenesis of the mitoribosome large subunit and consequently in mitochondrial translation. We report that RPUSD4 binds 16S mt-rRNA, mt-tRNA(Met), and mt-tRNA(Phe), and we demonstrate that it is responsible for pseudouridylation of the latter. These data provide new insights into the relevance of RNA pseudouridylation in mitochondrial gene expression.

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