Benzo(a)pyrene-caused increased G1-S transition requires the activation of c-Jun through p53-dependent PI-3K/Akt/ERK pathway in human embryo lung fibroblasts.
Benzo(a)pyrene (B(a)P) is a potent lung carcinogen mainly derived from tobacco smoking and environmental contamination, however, the molecular mechanisms by which it accelerates the cell cycle progression and induces the abnormal cell proliferation are still far away from understood. Our current analysis of human embryo lung fibroblasts (HELF) showed that B(a)P exposure was able to promote cell cycle G(1)-S phase transition. This effect was correlated with c-Jun activation because inhibition of c-Jun by its dominant negative mutant (TAM67) reversed B(a)P action on cell cycle with the down-regulation of expression of cyclin D1, pRb and E2F1. Further study found that overexpression of dominant negative mutants of, PI-3K or Akt, dramatically reduced B(a)P-induced the activation of c-Jun and extracellular signaling regulated kinase (ERK), but not c-Jun NH2 terminal kinase (JNK). Inhibition of p53 by either its inhibitor pifithrin-alpha or p53 siRNA markedly increased B(a)P-induced the activation of c-Jun, Akt and ERK in this context. Take together, our results indicate that c-Jun activation by p53-dependent PI-3K/Akt/ERK pathway is responsible for B(a)P-induced cell cycle alternations in human embryo lung fibroblasts.
Jiao
Shi
S
Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing, PR China.
Liu
Bingci
B
Gao
Ai
A
Ye
Meng
M
Jia
Xiaowei
X
Zhang
Fengmei
F
Liu
Haifeng
H
Shi
Xianglin
X
Huang
Chuanshu
C
D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000166:cytology / Q000196:embryology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D056741:Cyclin D; D016213:Cyclins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases