| First Author | Liu F | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 30 | Pages | 25530-40 |
| PubMed ID | 22669972 | Mgi Jnum | J:316425 |
| Mgi Id | MGI:6836794 | Doi | 10.1074/jbc.M112.356279 |
| Citation | Liu F, et al. (2012) NF-kappaB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. J Biol Chem 287(30):25530-40 |
| abstractText | 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-kappaB activation. Convincing experimental data have identified NF-kappaB as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-kappaB activity. On the other hand, compelling data have also shown that NF-kappaB activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-kappaB, the function of NF-kappaB 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-kappaB activation. Interestingly, canonical NF-kappaB was found to directly bind to the FAS promoter. Blocking canonical NF-kappaB activation diminished Fas expression, whereas blocking alternate NF-kappaB increased Fas expression in human carcinoma cells. Moreover, although canonical NF-kappaB protected mouse embryo fibroblast (MEF) cells from TNFalpha-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-kappaB is a Fas transcription activator and alternate NF-kappaB is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma. |
