Two distinct steps of Bak regulation during apoptotic stress signaling: different roles of MEKK1 and JNK1

Experimental Cell Research
Linda Strandberg IhrlundMaria C Shoshan

Abstract

Stress-activated protein (SAP) kinases and the mitochondrial pro-apoptotic Bcl-2 protein Bak are important regulators of apoptosis. Reduced expression of Bak increases cellular resistance to the anticancer agent cisplatin, and we report here that mouse embryo fibroblasts deficient in the SAP kinase jnk1 are highly resistant to apoptosis induced by cisplatin. When human melanoma cells were treated with cisplatin, Bak function was found to be regulated in two distinct steps by two SAP kinases, MEKK1 and JNK1. The first of these steps involves MEKK1-controlled conformational activation of Bak. The second step leads to formation of 80-170 kDa Bak complexes correlating with apoptosis, and is controlled by JNK1. Inhibition of MEKK1 blocked the initial Bak conformational activation but did not block JNK1 activation, and deficiency in, or inhibition of, JNK1 did not prevent conformational activation of Bak. Furthermore, inducible expression of a constitutively active form of MEKK1 led to Bak conformational activation, but not to 80-170 kDa complexes. Consequently, apoptosis was delayed unless JNK was exogenously stimulated, indicating that Bak conformational activation is not necessarily an apoptotic marker. The two-step regulation of ...Continue Reading

References

Apr 7, 1998·Molecular and Cellular Biology·C WidmannG L Johnson
Aug 13, 1999·Genes & Development·A GrossS J Korsmeyer
Aug 10, 2000·Trends in Cell Biology·S Desagher, J C Martinou
Jan 14, 2001·The Journal of Biological Chemistry·B AntonssonJ C Martinou
May 8, 2001·Molecular and Cellular Biology·A MandicM C Shoshan
Jul 12, 2001·The Journal of Biological Chemistry·G Q WangH Rabinowich
Jul 20, 2001·Journal of Virology·R Sundararajan, E White
Nov 28, 2002·The Journal of Biological Chemistry·Valery MikhailovPothana Saikumar
Jan 1, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Anning Lin
Feb 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Kui Lei, Roger J Davis
Jul 26, 2003·Science·Emily H Y ChengStanley J Korsmeyer

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Citations

Feb 13, 2007·Journal of Bioenergetics and Biomembranes·Dao M Nguyen, Mustafa Hussain
Sep 5, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lavinia LiguoriJean-Luc Lenormand
Apr 6, 2007·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Kristina Viktorsson, Rolf Lewensohn
Dec 7, 2007·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jürgen EberleLothar F Fecker

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