10-formyltetrahydrofolate dehydrogenase-induced c-Jun-NH2-kinase pathways diverge at the c-Jun-NH2-kinase substrate level in cells with different p53 status.

Molecular Cancer Research : MCR
Sampa GhoseSergey A Krupenko

Abstract

10-Formyltetrahydrofolate dehydrogenase (FDH) suppresses cancer cell proliferation through p53-dependent apoptosis but also induces strong cytotoxicity in p53-deficient prostate cells. In the present study, we have shown that FDH induces apoptosis in PC-3 prostate cells through simultaneous activation of the c-Jun-NH(2)-kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways with JNK phosphorylating c-Jun and ERK1/2 phosphorylating Elk-1. The JNK1/2 inhibitor SP600125 or ERK1/2 inhibitor PD98059 prevented phosphorylation of c-Jun and Elk-1, correspondingly and partially protected PC-3 cells from FDH-induced cytotoxicity. Combination of the two inhibitors produced an additive effect. The contribution from the JNK cascade to FDH-induced apoptosis was significantly stronger than from the ERK pathway. siRNA knockdown of JNK1/2 or "turning off" the downstream target c-Jun by either siRNA or expression of the dominant-negative c-Jun mutant, TAM67, rescued PC-3 cells from FDH-induced apoptosis. The pull-down assays on immobilized c-Jun showed that c-Jun is directly phosphorylated by JNK2 in FDH-expressing cells. Interestingly, the FDH-induced apoptosis in p53-proficient A549 cells also proceeds through activation of JNK1...Continue Reading

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Citations

Apr 17, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alexander P SobinoffEileen A McLaughlin
Jul 23, 2011·Genes & Cancer·Natalia V OleinikSergey A Krupenko
Aug 1, 2014·Cell Death & Disease·A PrakasamS A Krupenko
Jul 21, 2015·Biochemical and Biophysical Research Communications·Morihiko NakamuraKaori Notsu
Mar 23, 2013·The Journal of Biological Chemistry·L Alexis HoeferlinNatalia I Krupenko
Jul 28, 2019·International Journal of Molecular Sciences·Paul NoordhuisGodefridus J Peters
Feb 23, 2019·Chemico-biological Interactions·Sergey A Krupenko, Natalia I Krupenko

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