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Transient global cerebral ischemia induces up-regulation of MLTKα in hippocampal CA1 neurons

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Abstract

MLTK (mixed-lineage kinase-like mitogen-activated protein triple kinase) is a member of the mitogen-activated protein kinase family and functioned as a mitogen activated kinase kinase kinase. MLTKα, one of the alternatively spliced forms of MLTK, could activate the c-Jun N-terminal kinase pathway, which involved in cellular stress responses and apoptosis. But the role of MLTKα in neural apoptosis was still unclear. Here, we performed a transient global cerebral ischemia model (TGCI) in adult rats and detected the dynamic changes of MLTKα in hippocampal CA1 neurons and brain cortex. We found the MLTKα expression was increased shortly after TGCI and peaked after 8 h. In spatial distribution, MLTKα was widely located in neurons rather than astrocytes and microglia. Moreover, there was a concomitant up-regulation of active caspase-3. Taken together, we hypothesized the up-regulation of MLTKα played an essential role in the apoptosis of hippocampal CA1 neurons.

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Abbreviations

MLTK:

Mixed-lineage kinase-like mitogen-activated protein triple kinase

MAPK:

Mitogen-activated protein kinase

JNK:

C-Jun N-terminal kinase

TGCI:

Transient global cerebral ischemia

PAGE:

Polyacrylamide gel electrophoresis

ECL:

Enhanced chemiluminescence system

BSA:

Bovine serum albumin

DAB:

Diaminobenzidin

NeuN:

Neuronal nuclei

GFAP:

Glial fibrillary acidic protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

TUNEL:

Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling

References

  • Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH, Simon RP (1998) Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18:4914–4928

    PubMed  CAS  Google Scholar 

  • Chu CY, Xu BN, Huang WQ (2010) GnRH analogue attentuated apoptosis of rat hippocampal neuron after ischemia-reperfusion injury. J Mol Histol 41:387–393

    Article  PubMed  CAS  Google Scholar 

  • Clark RS, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, Melick J, Loeffert JE, Nathaniel PD, Jin KL, Graham SH (2000) Caspase-3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 74:740–753

    Article  PubMed  CAS  Google Scholar 

  • Erhardt L (1996) Biochemical markers in acute myocardial infarction–the beginning of a new era? Eur Heart J 17:1781–1782

    Article  PubMed  CAS  Google Scholar 

  • Fan G, Merritt SE, Kortenjann M, Shaw PE, Holzman LB (1996) Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. J Biol Chem 271:24788–24793

    Article  PubMed  CAS  Google Scholar 

  • Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Natl Rev Mol Cell Biol 3:663–672

    Article  CAS  Google Scholar 

  • Gelderblom M, Eminel S, Herdegen T, Waetzig V (2004) c-Jun N-terminal kinases (JNKs) and the cytoskeleton-functions beyond neurodegeneration. Int J Dev Neurosci 22:559–564

    Article  PubMed  CAS  Google Scholar 

  • Gotoh I, Adachi M, Nishida E (2001) Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem 276:4276–4286

    Article  PubMed  CAS  Google Scholar 

  • Gross EA, Callow MG, Waldbaum L, Thomas S, Ruggieri R (2002) MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem 277:13873–13882

    Article  PubMed  CAS  Google Scholar 

  • Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  PubMed  CAS  Google Scholar 

  • Hirai S, Katoh M, Terada M, Kyriakis JM, Zon LI, Rana A, Avruch J, Ohno S (1997) MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem 272:15167–15173

    Article  PubMed  CAS  Google Scholar 

  • Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–647

    Article  PubMed  CAS  Google Scholar 

  • Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J (1996) Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays 18:567–577

    Article  PubMed  CAS  Google Scholar 

  • Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ (2000) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun 274:811–816

    Article  PubMed  CAS  Google Scholar 

  • MacManus JP, Buchan AM, Hill IE, Rasquinha I, Preston E (1993) Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett 164:89–92

    Article  PubMed  CAS  Google Scholar 

  • Niizuma K, Endo H, Nito C, Myer DJ, Chan PH (2009) Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cerebral ischemia. Stroke 40:618–625

    Article  PubMed  CAS  Google Scholar 

  • Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E, Uchiyama Y (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15:1001–1011

    PubMed  CAS  Google Scholar 

  • Nozaki K, Nishimura M, Hashimoto N (2001) Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol 23:1–19

    Article  PubMed  CAS  Google Scholar 

  • Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y, Nakajo S, Matsumoto K (1999) Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 262:57–26260

    Article  PubMed  CAS  Google Scholar 

  • Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498

    Article  PubMed  CAS  Google Scholar 

  • Riedl SJ, Salvesen GS (2007) The apoptosome: signalling platform of cell death. Natl Rev Mol Cell Biol 8:405–413

    Article  CAS  Google Scholar 

  • Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186

    Article  PubMed  CAS  Google Scholar 

  • Sakuma H, Ikeda A, Oka S, Kozutsumi Y, Zanetta JP, Kawasaki T (1997) Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. J Biol Chem 272:28622–28629

    Article  PubMed  CAS  Google Scholar 

  • Smith ML, Bendek G, Dahlgren N, Rosen I, Wieloch T, Siesjo BK (1984) Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 69:385–401

    Article  PubMed  CAS  Google Scholar 

  • Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999) Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J Neurosci 19:RC39

    PubMed  CAS  Google Scholar 

  • Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Natl Rev Mol Cell Biol 9:231–241

    Article  CAS  Google Scholar 

  • Wang X, Mader MM, Toth JE, Yu X, Jin N, Campbell RM, Smallwood JK, Christe ME, Chatterjee A, Goodson T Jr, Vlahos CJ, Matter WF, Bloem LJ (2005) Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA. J Biol Chem 280:19298–19305

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Jian Chen.

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Xing Su and Chang-Lai Zhu contributed equally to this work.

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Su, X., Zhu, CL., Shi, W. et al. Transient global cerebral ischemia induces up-regulation of MLTKα in hippocampal CA1 neurons. J Mol Hist 43, 187–193 (2012). https://doi.org/10.1007/s10735-011-9381-z

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  • DOI: https://doi.org/10.1007/s10735-011-9381-z

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