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J Biol Chem ; 287(30): 25530-40, 2012 Jul 20.
Article in English | MEDLINE | ID: mdl-22669972

ABSTRACT

Fas is a member of the death receptor family. Stimulation of Fas leads to induction of apoptotic signals, such as caspase 8 activation, as well as "non-apoptotic" cellular responses, notably NF-κB activation. Convincing experimental data have identified NF-κB as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-κB activity. On the other hand, compelling data have also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-κB, the function of NF-κB in the Fas-mediated apoptosis pathway remains largely undefined. In this study, we observed that deficiency of either Fas or FasL resulted in significantly increased incidence of 3-methylcholanthrene-induced spontaneous sarcoma development in mice. Furthermore, Fas-deficient mice also exhibited significantly greater incidence of azoxymethane and dextran sodium sulfate-induced colon carcinoma. In addition, human colorectal cancer patients with high Fas protein in their tumor cells had a longer time before recurrence occurred. Engagement of Fas with FasL triggered NF-κB activation. Interestingly, canonical NF-κB was found to directly bind to the FAS promoter. Blocking canonical NF-κB activation diminished Fas expression, whereas blocking alternate NF-κB increased Fas expression in human carcinoma cells. Moreover, although canonical NF-κB protected mouse embryo fibroblast (MEF) cells from TNFα-induced apoptosis, knocking out p65 diminished Fas expression in MEF cells, resulting in inhibition of FasL-induced caspase 8 activation and apoptosis. In contrast, knocking out p52 increased Fas expression in MEF cells. Our observations suggest that canonical NF-κB is a Fas transcription activator and alternate NF-κB is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma.


Subject(s)
Apoptosis , Colonic Neoplasms/metabolism , NF-kappa B p52 Subunit/metabolism , Neoplasms, Experimental/metabolism , Sarcoma/metabolism , Transcription Factor RelA/metabolism , Tumor Suppressor Proteins/metabolism , fas Receptor/metabolism , Animals , Caspase 8/genetics , Caspase 8/metabolism , Colonic Neoplasms/chemically induced , Colonic Neoplasms/genetics , Embryo, Mammalian/metabolism , Embryo, Mammalian/pathology , Fas Ligand Protein/genetics , Fas Ligand Protein/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Methylcholanthrene/toxicity , Mice , Mice, Knockout , NF-kappa B p52 Subunit/genetics , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/genetics , Promoter Regions, Genetic/genetics , Sarcoma/chemically induced , Sarcoma/genetics , Sarcoma/pathology , Transcription Factor RelA/genetics , Tumor Suppressor Proteins/genetics , fas Receptor/genetics
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