NF-kappaB activation but not PI3K/Akt is required for dexamethasone dependent protection against TNF-alpha cytotoxicity in L929 cells.
Tumor necrosis factor alpha (TNF-alpha) is one of the best-described cell death promoters. In murine L929 fibroblasts, dexamethasone inhibits TNF-alpha-induced cytotoxicity. Since phosphatidyl inositol 3 kinase (PI3K) and nuclear factor kappa B (NF-kappaB) proteins regulate several survival pathways, we evaluated their participation in dexamethasone protection against TNF-alpha cell death. We interfered with these pathways by overexpressing a negative dominant mutant of PI3K or a non-degradable mutant of inhibitor of NF-kappaB alpha (IkappaBalpha) (the cytoplasmic inhibitor of NF-kappaB) in L929 cells. The mutant IkappaB, but not the mutant PI3K, abrogated dexamethasone-mediated protection. The loss of dexamethasone protection was associated with a diminished accumulation in XIAP and c-IAP proteins.
Mendoza-Milla
Criselda
C
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, México, D.F. 04510, México. cmendoza@ifc.unam.mx
Machuca Rodríguez
Catalina
C
Córdova Alarcón
Emilio
E
Estrada Bernal
Adriana
A
Toledo-Cuevas
E Mayra
EM
Martínez Martínez
Eduardo
E
Zentella Dehesa
Alejandro
A
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein
D005938:Glucocorticoids; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases