Bcl-x(L) suppresses TNF-mediated apoptosis and activation of nuclear factor-kappaB, activation protein-1, and c-Jun N-terminal kinase.
Tumor necrosis factor (TNF) is a multipotential cytokine that induces apoptosis and activates nuclear factor-kappa B (NF-kappaB), activation protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). Several mechanisms have been suggested to explain these effects of TNF, one of them being the involvement of reactive oxygen intermediates (ROI). Because Bcl-2 family members are known to affect the redox status of the cell, we examined the effect of Bcl-x(L) expression on TNF signaling. Overexpression of Bcl-x(L) in human promyelocytic lymphoma HL-60 cells downregulated TNF-induced cytotoxicity. Cleavage of poly (ADP-ribose) polymerase by caspases, an early indicator of apoptosis, was also blocked by Bcl-x(L) overexpression. Activation of NF-kappaB was significantly suppressed in cells overexpressing Bcl-x(L), as was degradation of IkappaBalpha, the inhibitory subunit of NF-kappaB. NF-kappaB activation induced by serum-activated lipopolysaccharide (SALPS), ceramide, and okadaic acid was also inhibited by overexpression of Bcl-x(L), whereas that by phorbol myristate acetate (PMA) and H2O2 was unaffected. Besides NF-kappaB, the activation of AP-1 by TNF also was blocked by Bcl-x(L). The activation of JNK and MAPK kinase, which regulate these transcription factors, was reduced in Bcl-x(L)-transfected cells. Overall, our results demonstrate that Bcl-x(L) inhibits TNF signaling at an early step common to induction of activation of apoptosis, NF-kappaB, AP-1, MAPK, and JNK.
Manna
S K
SK
Department of Molecular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Haridas
V
V
Aggarwal
B B
BB
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases