Bid mediates anti-apoptotic COX-2 induction through the IKKbeta/NFkappaB pathway due to 5-MCDE exposure.
Although Bid has been considered as a cell apoptotic mediator, current studies suggest a possible role in cell survival in mouse embryonic fibroblasts (MEFs) response to low doses of anti-(+/-)-5- methylchrysene-1,2-diol-3,4-epoxide(<or=0.25 microM) (5-MCDE). We found that exposure of MEFs to 0.25 microM 5-MCDE resulted in a slight apoptotic induction, while this apoptotic response was substantially increased in the Bid knockout MEFs (Bid(-/-)), suggesting Bid-mediated anti-apoptotic function in this response. This notion was further supported by the findings that re-constitution expression of Bid into Bid(-/-) cells could inhibit the increased apoptosis. Further studies showed that Bid anti-apoptotic function was associated with its mediation of COX-2 expression, which was based on the results of the reduction of COX-2 expression in Bid(-/-) cells, restoration of low sensitivity to 5-MCDE apoptotic response by the introduction of Bid into Bid(-/-) cells and increased sensitivity of WT MEFs to 5-MCDE apoptosis by knockdown of COX-2 expression. Furthermore, Bid mediated COX-2 expression through the IKKbeta/NFkappaB pathway because the deficiency of Bid in Bid(-/-) MEFs resulted in blockade of IKK/NFkappaB activation and knockout of IKKbeta caused abrogation of COX-2 expression induced by 5-MCDE. Collectively, our results demonstrate that Bid is critical for COX-2 induction through the IKKbeta/NFkappaB pathway, which mediates its anti-apoptotic function, in cell response to low doses of 5-MCDE exposure.
Luo
Wenjing
W
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Li
Jingxia
J
Zhang
Dongyun
D
Cai
T
T
Song
Lun
L
Yin
Xiao-Ming
XM
Desai
Dhimant
D
Amin
Shantu
S
Chen
Jingyuan
J
Huang
Chuanshu
C
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D002911:Chrysenes / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; D002273:Carcinogens; D002911:Chrysenes; D016328:NF-kappa B; C037783:1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase