MAPK kinase kinase-1 is essential for cytokine-induced c-Jun NH2-terminal kinase and nuclear factor-kappaB activation in human pancreatic islet cells.

Diabetes
Dariush MokhtariNils Welsh

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases (MAPKs) c-Jun NH(2)-terminal kinase (JNK) 1/2 are known to play decisive roles in cytokine-induced damage of rodent beta-cells. The upstream events by which these factors are activated in response to cytokines are, however, uncharacterized. The aim of the present investigation was to elucidate a putative role of the MAPK kinase kinase-1 (MEKK-1) in cytokine-induced signaling. To establish a functional role of MEKK-1, the effects of transient MEKK-1 overexpression in betaTC-6 cells, achieved by lipofection and cell sorting, and MEKK-1 downregulation in betaTC-6 cells and human islet cells, achieved by diced-small interfering RNA treatment, were studied. We observed that overexpression of wild-type MEKK-1, but not of a kinase dead MEKK-1 mutant, resulted in potentiation of cytokine-induced JNK activation, inhibitor of kappaB (IkappaB) degradation, and cell death. Downregulation of MEKK-1 in human islet cells provoked opposite effects, i.e., attenuation of cytokine-induced JNK and MKK4 activation, IkappaB stability, and a less pronounced NF-kappaB translocation. betaTC-6 cells with a downregulated MEKK-1 expression displayed also a...Continue Reading

References

Sep 27, 1994·Proceedings of the National Academy of Sciences of the United States of America·D L EizirikA Andersson
Oct 1, 1994·The Journal of Clinical Endocrinology and Metabolism·A RabinovitchR V Rajotte
May 3, 1996·Cell·R Tisch, H McDevitt
Aug 15, 1997·The EMBO Journal·G R FangerG L Johnson
Apr 7, 1998·Molecular and Cellular Biology·C WidmannG L Johnson
Mar 14, 2000·Molecular and Cellular Biology·S P HehnerM L Schmitz
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y XiaM Karin
Mar 29, 2001·Diabetes·D L Eizirik, M I Darville
May 23, 2001·The Journal of Biological Chemistry·J W KimE J Choi
Jan 17, 2002·Diabetologia·D L Eizirik, T Mandrup-Poulsen
Mar 5, 2002·Nature Immunology·Michael Karin, Anning Lin
Oct 9, 2003·The Journal of Biological Chemistry·Shaoping ZhangGarth J S Cooper
Jan 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Deepa R HammakerGary S Firestein
May 3, 2005·Nature Reviews. Immunology·Leonidas C Platanias
May 14, 2005·Annals of the New York Academy of Sciences·Robert HägerkvistNils Welsh
Jul 2, 2005·Methods in Molecular Biology·Jason W Myers, James E Ferrell
Aug 16, 2005·The Biochemical Journal·Natalia MakeevaNils Welsh
Mar 23, 2006·Proceedings of the National Academy of Sciences of the United States of America·R EldorD Melloul
Jun 15, 2007·Arthritis Research & Therapy·Deepa R HammakerGary S Firestein
Jul 7, 2007·Journal of Liposome Research·Andreea Barbu, Nils Welsh

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Citations

Jul 2, 2009·The Journal of Clinical Endocrinology and Metabolism·Vladimir K BakalovCarolyn A Bondy
Sep 8, 2010·Hematology/oncology Clinics of North America·Zsofia K StadlerKenneth Offit
Sep 6, 2013·Biochimica Et Biophysica Acta·Srividya VasuPeter R Flatt
Sep 28, 2018·PloS One·Anna Lindeløv VestergaardThomas Mandrup-Poulsen

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Methods Mentioned

BETA
biopsies
FCS
in vitro transcription
transfection
fluorescence microscopy
electrophoresis
electromobility shift assay
fluorescence-activated
immunoprecipitation
nuclear translocation

Software Mentioned

Kodak Digital Science ID
NIH Image
Openlab

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