Calcium/Calmodulin-dependent protein kinase II regulation of c-FLIP expression and phosphorylation in modulation of Fas-mediated signaling in malignant glioma cells

• Verfasst von: Yang, Bao Feng [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Titel: Calcium/Calmodulin-dependent protein kinase II regulation of c-FLIP expression and phosphorylation in modulation of Fas-mediated signaling in malignant glioma cells
• Verf.angabe: Bao Feng Yang, Chang Xiao, Wilson H. Roa, Peter H. Krammer, and Chunhai Hao
• Jahr: 2003
• Umfang: 8 S.
• Teil: volume:278
• Teil: year:2003
• Teil: number:9
• Teil: pages:7043-7050
• Teil: extent:8
• Fussnoten: Available online 4 January 2021 ; Elektronische Reproduktion der Druck-Ausgabe ; Gesehen am 07.04.2021
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : Soc., 1905
• Jahr Quelle: 2003
• Band/Heft Quelle: 278(2003), 9, Seite 7043-7050
• ISSN Quelle: 1083-351X
• DOI: doi:10.1074/jbc.M211278200
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1753278430

Abstract

Fas, upon cross-linking with Fas ligand (FasL) or Fas agonistic antibody, transduces apoptotic yet also proliferative signals, which have been implicated in tumor pathogenesis. In this study, we investigated the molecular mechanisms that control Fas-mediated signaling in glioma cells. Fas agonistic antibody, CH-11, induced apoptosis in sensitive glioma cells through caspase-8 recruitment to the Fas-mediated death-inducing signaling complex (DISC) where caspase-8 was cleaved to initiate apoptosis through a systematic cleavage of downstream substrates. In contrast, CH-11 stimulated cell growth in resistant glioma cells through recruitment of c-FLIP (cellular Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE)-inhibitory protein) to the Fas-mediated DISC. Three isoforms of long form c-FLIP were detected in glioma cells, but only the phosphorylated isoform was recruited to and cleaved into a p43 intermediate form in the Fas-mediated DISC in resistant cells. Calcium/calmodulin-dependent protein kinase II (CaMK II) activity was up-regulated in resistant cells. Treatment of resistant cells with the CaMK II inhibitor KN-93 inhibited CaMK II activity, reduced c-FLIP expression, inhibited c-FLIP phosphorylation, and rescued CH-11 sensitivity. Transfection of CaMK II cDNA in sensitive cells rendered them resistant to CH-11. These results indicated that CaMK II regulates c-FLIP expression and phosphorylation, thus modulating Fas-mediated signaling in glioma cells.