Skip to main content

Advertisement

SpringerLink
Log in

TNFα-induced DLK activation contributes to apoptosis in the beta-cell line HIT

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT. In the present study, it was investigated whether TNFα or IL-1β stimulates DLK enzymatic activity. Immunoblot analysis, transient transfection with luciferase reporter gene assays, and immunofluorescence were used. In contrast to IL-1β, TNFα stimulated DLK kinase activity, which was dependent on the c-Jun N-terminal kinase (JNK). Furthermore, DLK contributed to TNFα-induced JNK phosphorylation. The phosphorylation of DLK on Ser-302 within the activation loop was required for DLK to stimulate JNK and to inhibit CREB-dependent gene transcription. TNFα induced apoptosis in a time- and concentration-dependent manner and inhibited CREB-directed gene transcription in HIT cells. The reduction of endogenous DLK by small interfering or small hairpin RNA attenuated TNFα’s effects on apoptosis and CREB-dependent transcription. These data suggest that TNFα induces beta-cell apoptosis through activation of DLK thereby inhibiting the beta-cell protective transcription factor CREB. Furthermore, activation of DLK by a well-known diabetic risk factor supports the role of DLK in the pathogenesis of diabetes mellitus. Thus, the inhibition of DLK might prevent or retard the pathogenesis of diabetes mellitus type 2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CBP:

CREB binding protein

CRE:

cAMP responsive element

CREB:

CRE binding protein

CRIB:

Rac/Cdc42 interaction site

CRTC:

cAMP regulated transcriptional coactivator

DLK:

Dual leucine zipper kinase

IL-1β:

Interleukin-1β

JIP/IB-1:

JNK interacting protein/islet-brain-1

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MLK:

Mixed lineage kinase

NFκB:

Nuclear factor κ B

TNFα:

Tumor necrosis factor α

TRAF6:

TNFα receptor-associated factor 6

References

  • Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) SP600125, an anthrapyrazolone inhibitor of Jun N terminal kinase. Proc Natl Acad Sci U S A 98:13681–13686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blanchet E, Van de Velde S, Matsumura S, Hao E, LeLay J, Kaestner K, Montminy M (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blondeau A, Lucier J-F, Matteau D, Dumont L, Rodrigue S, Jacques P-É, Blouin R (2016) Dual leucine zipper kinase regulates expression of axon guidance genes in mouse neuronal cells. Neural Dev 11:13

    Article  PubMed  PubMed Central  Google Scholar 

  • Bouzakri K, Ribaux P, Halban PA (2009) Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-α-induced decrease of IRS-2 and inhibition of glucose stimulated insulin secretion. J Biol Chem 284:27892–27898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenner D, Blaser H, Mak TW (2015) Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol 15:362–374

    Article  CAS  PubMed  Google Scholar 

  • Brooks-Worrell B, Narla R, Palmer JP (2012) Biomarkers and immune-modulating therapies for type 2 diabetes. Trends Immunol 33:546–553

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Rzhetskaya M, Kareva T, Bland R, During MJ, Tank AW, Kholodilov N, Burke RE (2008) Antiapoptotic and trophic effects of dominant-negative forms of dual leucine zipper kinase in dopamine neurons of the substantia nigra in vivo. Journal Neurosci 28:672–680

    Article  CAS  Google Scholar 

  • Coffey ET (2014) Nuclear and cytosolic JNK signalling in neurons. Nat Rev Neurosci 15:285–299

    Article  CAS  PubMed  Google Scholar 

  • Cohen P (2014) The TLR and IL-1 signalling network at a glance. J Cell Sci 127:2383–2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couture J-P, Daviau A, Fradette J, Blouin R (2009) The mixed-lineage kinase DLK is a key regulator of 3T3 L1 adipocyte differentiation. PLoS One 4:e4743

    Article  PubMed  PubMed Central  Google Scholar 

  • Craige SM, Reif MM, Kant S (2016) Mixed – lineage protein kinases (MLKs) in inflammation, metabolism, and other disease states. Biochim Biophys Act 1862:1581–1586

    Article  CAS  Google Scholar 

  • Dalle S, Quoyer J, Varin E, Costes S (2011) Roles and regulation of the transcription factor CREB in pancreatic beta-cells. Curr Mol Pharmacol 4:187–195

    Article  CAS  PubMed  Google Scholar 

  • Daviau A, Proulx R, Robitaille K, Di Fruscio M, Tanguay RM, Landry J, Patterson C, Durocher Y, Blouin R (2006) Down-regulation of the mixed-lineage dual leucine zipper-bearing kinase by heat shock protein 70 and its co-chaperone CHIP. J Biol Chem 281:31467–31477

    Article  CAS  PubMed  Google Scholar 

  • Donath MY (2014) Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 13:465–476

    Article  CAS  PubMed  Google Scholar 

  • Donath MY (2016) Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia 59:679–682

    Article  CAS  PubMed  Google Scholar 

  • Ferraris D, Yang Z, Welsbie D (2013) Dual leucine zipper kinase as a therapeutic target for neurodegenerative conditions. Future Med Chem 5:1923–1934

    Article  CAS  PubMed  Google Scholar 

  • Feve B, Bastard J-P (2009) The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 5:305–311

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hao Y, Frey E, Yoon C, Wong H, Nestorovski D, Holzman LB, Giger RJ, DiAntonio A, Collins C (2016) An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. elife 5:e14048

    Article  PubMed  PubMed Central  Google Scholar 

  • Hébert SS, Daviau A, Grondin G, Latreille M, Aubin RA, Blouin R (2000) The mixed lineage kinase DLK is oligomerized by tissue transglutaminase during apoptosis. J Biol Chem 275:32482–32490

    Article  PubMed  Google Scholar 

  • Hirai S, Cui de F, Miyata T, Ogawa M, Kiyonari H, Suda Y, Aizawa S, Banba Y, Ohno S (2006) The c-Jun N terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J Neurosci 26:11992–12002

    Article  CAS  PubMed  Google Scholar 

  • Holland SM, Collura KM, Ketschek A, Noma K, Ferguson TA, Jin Y, Gallo G, Thomas GM (2016) Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling. Proc Natl Acad Sci U S A 113:763–768

    Article  CAS  PubMed  Google Scholar 

  • Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha J Clin Invest 94:1543–1549

    CAS  PubMed  Google Scholar 

  • Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95:2409–2415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665–670

    Article  CAS  PubMed  Google Scholar 

  • Hsieh Y-C, Chen Y-H, Jao H-C, Hsu H-K, Huang L-J, Hsu C (2005) Role of cAMP-response element-binding protein phosphorylation in hepatic apoptosis under protein kinase Cα suppression during sepsis. Shock 24:357–363

    Article  CAS  PubMed  Google Scholar 

  • Huang Y-WA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. doi:10.1016/j.cell.2016.12.044

  • Humphrey RK, Yu SMA, Bellary A, Gonuguntla S, Yebra M, Jhala US (2013) Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic β cell death. J Biol Chem 288:2428–2440

    Article  CAS  PubMed  Google Scholar 

  • Huntwork-Rodriguez S, Wang B, Watkins T, Ghosh AS, Pozniak CD, Bustos D, Newton K, Kirkpatrick DS, Lewcock JW (2013) JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. J Cell Biol 202:747–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imai Y, Dobrian AD, Morris MA, Nadler JL (2013) Islet inflammation: a unifying target for diabetes treatment? Trends Endocrinol Metab 24:351–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jansson D, Ng AC-H, Fu A, Depatie C, Al Azzabi M, Screaton RA (2008) Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proc Natl Acad Sci U S A 105:10161–10166

    Article  PubMed  PubMed Central  Google Scholar 

  • Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kahn SE, Zraika S, Utzschneider KM, Hull RL (2009) The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52:1003–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kant S, Swat W, Zhang S, Zhang Z-Y, Neel BG, Flavell RA, Davis RJ (2011) TNF-stimulated MAP kinase activation mediated by a rho family GTPase signaling pathway. Genes Dev 25:2069–2078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Nian C, Widenmaier S, McIntosh CH (2008) Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 28:1644–1656

    Article  CAS  PubMed  Google Scholar 

  • Korchnak AC, Zhan Y, Aguilar MT, Chadee DN (2009) Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cell Signal 21:1620–1625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY (2007) Interleukin-1–receptor antagonist in type 2 diabetes mellitus. N Engl J Medicine 356(1517):1526

    Google Scholar 

  • Leung IW-L, Lassam N (2001) The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoetic progenitor kinase 1 phosphorylation. J Biol Chem 276:1961–1967

    Article  CAS  PubMed  Google Scholar 

  • Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY (2002) Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malm HA, Mollet IG, Berggreen C, Orho-Melander M, Esguerra JLS, Göransson O, Eliasson L (2016) Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting β-cells by cAMP regulated transcriptional co-activator 1 and salt-inducible kinases. Mol Cell Endocrinol 424:23–33

  • Melloul D (2008) Role of NF-κB in β-cell death. Biochem Soc Trans 36:334–339

    Article  CAS  PubMed  Google Scholar 

  • Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A (2009) A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci 12:387–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nihalani D, Merritt S, Holzman LB (2000) Identification of structural and functional domains in mixed lineage kinase dual leucine zipper-bearing kinase required for complex formation and stress activated protein kinase activation. J Biol Chem 275:7273–7279

    Article  CAS  PubMed  Google Scholar 

  • Nihalani D, Meyer D, Pajni S, Holzman LB (2001) Mixed lineage kinase-dependent JNK activation is governed by interactions of scaffold protein JIP with MAPK module components. EMBO J 20:3447–3458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nihalani D, Wong HN, Holzman LB (2003) Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation. J Biol Chem 278:28694–28702

    Article  CAS  PubMed  Google Scholar 

  • Nihalani D, Wong H, Verma R, Holzman LB (2007) Src family kinases directly regulate JIP1 module dynamics and activation. Mol Cell Biol 27:2431–2441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oetjen E, Lemcke T (2016) Dual leucine zipper kinase (MAP3K12) modulators: a patent review (2010–2015). Expert Opin Ther Pat 26:607–616

    Article  CAS  PubMed  Google Scholar 

  • Oetjen E, Diedrich T, Eggers A, Eckert B, Knepel W (1994) Distinct properties of the cAMP-responsive element of the rat insulin I gene. J Biol Chem 269:27036–27044

    CAS  PubMed  Google Scholar 

  • Oetjen E, Baun D, Beimesche S, Krause D, Cierny I, Blume R, Dickel C, Wehner S, Knepel W (2003a) Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice. Mol Pharmacol 63:1289–1295

    Article  CAS  PubMed  Google Scholar 

  • Oetjen E, Grapentin D, Blume R, Seeger M, Krause D, Eggers A, Knepel W (2003b) Regulation of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus at concentrations that inhibit calcineurin activity and involving the transcription factor CREB. Naunyn Schmiedeberg’s Arch Pharmacol 367:227–236

    Article  CAS  Google Scholar 

  • Oetjen E, Lechleiter A, Blume R, Nihalani D, Holzman L, Knepel W (2006) Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line. Diabetologia 49:332–342

    Article  CAS  PubMed  Google Scholar 

  • Oetjen E, Blume R, Cierny I, Schlag C, Kutschenko A, Kratzner R, Stein R, Knepel W (2007) Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1beta and mitogen activated protein kinase kinase kinase in pancreatic islet beta cells. Diabetologia 50:1678–1687

    Article  CAS  PubMed  Google Scholar 

  • Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, Théâtre E, Verhaeghe C, Magnusson NE, Chariot A, Ørntoft TF, Eizirik DL (2008) Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells. Diabetologia 51:1213–1225

    Article  CAS  PubMed  Google Scholar 

  • Parkash J, Chaudhry MA, Rhoten WB (2005) Tumor necrosis factor-α-induced changes in insulin-producing β cells. Anat Rec A: Discov Mol Cell Evol Biol 286A:982–993

    Article  CAS  Google Scholar 

  • Patel S, Cohen F, Dean BJ, De La Torre K, Deshmukh G, Estrada AA, Ghosh AS, Gibbons P, Gustafson A, Huestis MP, Le Pichon CE, Lin H, Liu W, Liu X, Liu Y, Ly CQ, Lyssikatos JP, Ma C, Scearce-Levie K, Shin YG, Solanoy H, Stark KL, Wang J, Wang B, Zhao X, Lewcock JW, Siu M (2015) Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J Med Chem 58:401–418

    Article  CAS  PubMed  Google Scholar 

  • Phu DT, Wallbach M, Depatie C, Fu A, Screaton RA, Oetjen E (2011) Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels. Cell Signal 23:344–353

    Article  CAS  Google Scholar 

  • Plaumann S, Blume R, Borchers S, Steinfelder HJ, Knepel W, Oetjen E (2008) Activation of the dual-leucine zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A. Mol Pharmacol 73:652–659

    Article  CAS  PubMed  Google Scholar 

  • Pozniak CD, Sengupta Ghosh A, Gogineni A, Hanson JE, Lee S-H, Larson JL, Solanoy H, Bustos D, Li H, Ngu H, Jubb AM, Ayalon G, Wu J, Scearce-Levie K, Zhou Q, Weimer RM, Kirkpatrick DS, Lewcock JW (2013) Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. J Exp Med 210:2553–2567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robitaille K, Daviau A, Tucholski J, Johnson GVW, Rancourt C, Blouin R (2004) Tissue transglutaminase triggers oligomerization and activation of dual leucine zipper-bearing kinase in calphostin C-treated cells to facilitate apoptosis. Cell Death Differ 11:542–549

    Article  CAS  PubMed  Google Scholar 

  • Santerre RF, Cook RA, Crisel RM, Sharp JD, Schmidt RJ, Williams DC, Wilson CP (1981) Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cells. Proc Natl Acad Sci U S A 78:4339–4343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar SA, Kutlu B, Velmurugan K, Kizaka-Kondoh S, Lee CE, Wong R, Valentine A, Davidson HW, Hutton JC, Pugazhenthi S (2009) Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line. Diabetologia 52(1092):1101

    Google Scholar 

  • Schmitz ML, Weber A, Roxlau T, Gaestel M, Kracht M (2011) Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. Biochim Biophys Act 1813:2165–2175

    Article  CAS  Google Scholar 

  • Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A (2012) Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74:1015–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin S, Le Lay J, Everett LJ, Gupta R, Rafiq K, Kaestner KH (2014) CREB mediates the insulinotropic and anti apoptotic effects of GLP-1 signaling in adult mouse beta-cells. Mol Metab 3:803–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stahnke MJ, Dickel C, Schroder S, Kaiser D, Blume R, Stein R, Pouponnot C, Oetjen E (2014) Inhibition of human insulin gene transcription and MafA transcriptional activity by the dual leucine zipper kinase. Cell Signal 26:1792–1799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tedeschi A, Bradke F (2013) The DLK signalling pathway[mdash]a double-edged sword in neural development and regeneration. EMBO Rep 14:605–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valakh V, Walker LJ, Skeath JB, DiAntonio A (2013) Loss of the Spectraplakin short stop activates the DLK injury response pathway in drosophila. J Neurosci 33:17863–17873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vallerie SN, Hotamisligil GS (2010) The role of JNK proteins in metabolism. Sci Transl Med 2:60rv65–60rv65

    Article  Google Scholar 

  • Wallbach M, Duque Escobar J, Babaeikelishomi R, Stahnke MJ, Blume R, Schroder S, Kruegel J, Maedler K, Kluth O, Kehlenbach RH, Miosge N, Oetjen E (2016) Distinct functions of the dual leucine zipper kinase depending on its subcellular localization. Cell Signal 28:272–283

    Article  CAS  PubMed  Google Scholar 

  • Watkins TA, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z, Eastham-Anderson J, Modrusan Z, Kaminker JS, Tessier-Lavigne M, Lewcock JW (2013) DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci U S A 110:4039–4044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci Signal 3:cm1

    PubMed  Google Scholar 

  • Welsbie DS, Yang Z, Ge Y, Mitchell KL, Zhou X, Martin SE, Berlinicke CA, Hackler L Jr, Fuller J, Fu J, Cao LH, Han B, Auld D, Xue T, Hirai S, Germain L, Simard-Bisson C, Blouin R, Nguyen JV, Davis CH, Enke RA, Boye SL, Merbs SL, Marsh-Armstrong N, Hauswirth WW, DiAntonio A, Nickells RW, Inglese J, Hanes J, Yau KW, Quigley HA, Zack DJ (2013) Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death. Proc Natl Acad Sci U S A 110:4045–4050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeke A, Misheva M, Reményi A, Bogoyevitch MA (2016) JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev 80:793–835

    Article  PubMed  Google Scholar 

  • Zhang S, Kim K-H (1995) TNF-α inhibits glucose-induced insulin secretion in a pancreatic β-cell line (INS-1). FEBS Lett 377:237–239

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Markus Schwaninger (Lübeck, Germany) for the kind gift of the NFκB DNA binding-site luciferase reporter gene, Larry Holzman (Philadelphia, USA) for his generous gift of the antibody against the C-terminus of DLK, Richard Blouin (Québec, Canada) for the gift of the shRNA expressing plasmids, Ingke Braren (Hamburg, Germany) for the preparation of the lentiviral transduced HIT-cells, and Edzard Schwedhelm (Hamburg, Germany) for critically reading the manuscript. The present study was supported by grants from the Deutsche Forschungsgemeinschaft (OE 181/3-1) and the Institut Danone Ernährung für Gesundheit e.V..

Author information

Author notes

  1. Rohollah Babaei

    Present address: DKFZ Heidelberg, Heidelberg, Germany

  2. Muhammad Nasir Hayat Malik

    Present address: Twincore, Center for Experimental and Clinical Infection Research, Hannover, Germany

Authors and Affiliations

  1. Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    Svenja Börchers, Rohollah Babaei, Catarina Klimpel, Roland Blume & Elke Oetjen

  2. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Rohollah Babaei, Jorge Duque Escobar, Sabine Schröder, Muhammad Nasir Hayat Malik & Elke Oetjen

  3. DZHK (German Center for Cardiovascular Research) Partner-site Hamburg/Kiel/Lübeck, Institute of Clinical Pharmacology and Toxicology, Hamburg, Germany

    Jorge Duque Escobar & Elke Oetjen

  4. Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146, Hamburg, Germany

    Elke Oetjen

Authors
  1. Svenja Börchers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohollah Babaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catarina Klimpel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jorge Duque Escobar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabine Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roland Blume
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Muhammad Nasir Hayat Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elke Oetjen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elke Oetjen.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

ESM 1

(PDF 1352 kb)

ESM 2

(PDF 1439 kb)

ESM 3

(PDF 1479 kb)

ESM 4

(PDF 1364 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Börchers, S., Babaei, R., Klimpel, C. et al. TNFα-induced DLK activation contributes to apoptosis in the beta-cell line HIT. Naunyn-Schmiedeberg's Arch Pharmacol 390, 813–825 (2017). https://doi.org/10.1007/s00210-017-1385-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-017-1385-0

Keywords

Search

Navigation