Abstract
Dlk/ZIP kinase is a member of the Death Associated Protein (DAP) kinase family of pro-apoptotic serine/threonine kinases that have been implicated in regulation of apoptosis and tumour suppression. Expression of both Dlk/ZIP kinase and its interaction partner Par-4 is maintained in four medulloblastoma cell lines investigated, whereas three of seven neuroblastoma cell lines have lost expression of Par-4. Overexpression of a constitutively pro-apoptotic deletion mutant of Dlk/ZIP kinase induced significant apoptosis in D283 medulloblastoma cells. Cell death was characterized by apoptotic membrane blebbing, and a late stage during which the cells had ceased blebbing and were drastically shrunken or disrupted into apoptotic bodies. Over-expression of the anti-apoptotic Bcl-xL protein had no effect on Dlk/ZIP kinase-induced membrane blebbing, but potently inhibited Dlk/ZIP kinase-induced cytochrome c release and transition of cells to late stage apoptosis. Treatment with caspase inhibitors delayed, but did not prevent entry into late stage apoptosis. These results demonstrate that Dlk/ZIP kinase-triggered apoptosis involves the mitochondrial apoptosis pathway. However, cell death proceeded in the presence of caspase inhibitors, suggesting that Dlk/ZIP kinase is able to activate alternative cell death pathways. Alterations of signal transduction pathways leading to Dlk/ZIP kinase induced apoptosis or loss of expression of upstream activators could play important roles in tumour progression and metastasis of neural tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Ashkenazi A and Dixit VM (1998) Death receptors: signaling and modulation. Science 281: 1305–1308
Berra E, Municio MM, Sanz L, Frutos S, Diaz-Meco MT and Moscat J (1997) Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade. Mol Cell Biol 17: 4346–4354
Borner C and Monney L (1999) Apoptosis without caspases: an inefficient molecular guillotine?. Cell Death Differ 6: 497–507
Camandola S and Mattson MP (2000) Pro-apoptotic action of PAR-4 involves inhibition of NF-kappaB activity and suppression of BCL-2 expression. J Neurosci Res 61: 134–139
Cecconi F (1999) Apaf1 and the apoptotic machinery. Cell Death Differ 6: 1087–1098
Cohen O, Feinstein E and Kimchi A (1997) DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. Embo J 16: 998–1008
Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H, Spivak-Kroizaman T, Feinstein E and Kimchi A (1999) DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol 146: 141–148
Cohen O and Kimchi A (2001) DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death Differ 8: 6–15
Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A and Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK 1. Nat Cell Biol 3: 339–345
Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M and Lord JM (2000) Serine/threonine protein kinases and apoptosis. Exp Cell Res 256: 34–41
Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J and Kroemer G (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14: 729–739
Deiss LP, Feinstein E, Berissi H, Cohen O and Kimchi A (1995) Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 9: 15–30
Desagher S and Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10: 369–377
Diaz-Meco MT, Lallena MJ, Monjas A, Frutos S and Moscat J (1999) Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis. J Biol Chem 274: 19606–19612
Du C, Fang M, Li Y, Li L and Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102: 33–42
Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM and Mattson MP (1999) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4: 957–962
Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W and Paolo Pandolfi P (2000) The function of PML in p53-dependent apoptosis. Nat Cell Biol 2: 730–736
Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L and Kimchi A (1997) DAP kinase links the control of apoptosis to metastasis. Nature 390: 180–184
Inbal B, Shani G, Cohen O, Kissil JL and Kimchi A (2000) Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol Cell Biol 20: 1044–1054
Kawai T, Matsumoto M, Takeda K, Sanjo H and Akira S (1998) ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol Cell Biol 18: 1642–1651
Kawai T, Nomura F, Hoshino K, Copeland NG, Gilbert DJ, Jenkins NA and Akira S (1999) Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity. Oncogene 18: 3471–3480
Kissil JL, Feinstein E, Cohen O, Jones PA, Tsai YC, Knowles MA, Eydmann ME and Kimchi A (1997) DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene 15: 403–407
Kögel D, Plöttner O, Landsberg G, Christian S and Scheidtmann KH (1998) Cloning and characterization of DIk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones. Oncogene 17: 2645–2654
Kögel D, Bierbaum H, Preuss U and Scheidtmann KH (1999) C-terminal truncation of DIk/ZIP kinase leads to abrogation of nuclear transport and high apoptotic activity. Oncogene 18: 7212–7218
Kögel D, Prehn JH and Scheidtmann KH (2001) The DAP kinase family of pro-apoptotic proteins: novel players in the apoptotic game. Bioessays 23: 352–358
Kroemer G (1999) Cytochrome c. Curr Biol 9: R468
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479–489
Liu X, Kim CN, Yang J, Jemmerson R and Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86: 147–157
Loeffler M and Kroemer G (2000) The mitochondrion in cell death control: certainties and incognita. Exp Cell Res 256: 19–26
Luetjens CM, Bui NT, Sengpiel B, Munstermann G, Poppe M, Krohn AJ, Bauerbach E, Krieglstein J and Prehn JH (2000) Delayed mitochondrial dysfunction in excitotoxic neuron death: cytochrome c release and a secondary increase in superoxide production. J Neurosci 20: 5715–5723
Mattson MP, Duan W, Chan SL and Camandola S (1999) Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. J Mol Neurosci 13: 17–30
McCarthy NJ, Whyte MK, Gilbert CS and Evan GI (1999) Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol 136: 215–227
Mills JC, Stone NL, Erhardt J and Pittman RN (1998) Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation. J Cell Biol 140: 627–636
Mills JC, Stone NL and Pittman RN (1999) Extranuclear apoptosis. The role of the cytoplasm in the execution phase. J Cell Biol 146: 703–708
Murata-Hori M, Suizu F, Iwasaki T, Kikuchi A and Hosoya H (1999) ZIP kinase identified as a novel myosin regulatory light chain kinase in HeLa cells. FEBS Lett 451: 81–84
Page G, Kögel D, Rangnekar V and Scheidtmann KH (1999a) Interaction partners of DIk/ZIP kinase: co-expression of DIk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. Oncogene 18: 7265–7273
Page G, Lödige I, Kögel D and Scheidtmann KH (1999b) AATF, a novel transcription factor that interacts with DIk/ZIP kinase and interferes with apoptosis. FEBS Lett 462: 187–191
Poppe M, Reimertz C, Krohn AJ, Luetjens CM, Böckelmann D, Nieminen A-L, Kögel D and Prehn JHM (2001) Dissipation of mitochondrial potassium and proton gradients inhibits cytochrome c release during neuronal apoptosis. J Neurosci 21: 4551–4563
Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC and de The H (1998) PML induces a novel caspase-independent death process. Nat Genet 20: 259–265
Sanjo H, Kawai T and Akira S (1998) DRAKs, novel serine/threonine kinases related to death-associated protein kinase that trigger apoptosis. J Biol Chem 273: 29066–29071
Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J and Breard J (2001) Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 3: 346–352
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43–53
Zou H, Henzel WJ, Liu X, Lutschg A and Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90: 405–413
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Kögel, D., Reimertz, C., Mech, P. et al. Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway. Br J Cancer 85, 1801–1808 (2001). https://doi.org/10.1054/bjoc.2001.2158
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2158
Keywords
This article is cited by
-
Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells
Cancer Cell International (2016)
-
Zipper interacting protein kinase (ZIPK): function and signaling
Apoptosis (2014)
-
The DAPK family: a structure–function analysis
Apoptosis (2014)
-
Expression of PAR-4 and PHLDA1 is prognostic for overall and disease-free survival in oral squamous cell carcinomas
Virchows Archiv (2013)
-
Cancer-selective apoptotic effects of extracellular and intracellular Par-4
Oncogene (2010)