Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.
Frequent exposure to nickel compounds has been considered as one of the potential causes of human lung cancer. However, the molecular mechanism of nickel-induced lung carcinogenesis remains obscure. In the current study, slight S-phase increase, significant G(2)/M cell cycle arrest, and proliferation blockage were observed in human bronchial epithelial cells (Beas-2B) upon nickel exposure. Moreover, the induction of cyclin D1 and cyclin E by nickel was shown for the first time in human pulmonary cells, which may be involved in nickel-triggered G(1)/S transition and cell transformation. In addition, we verified that hypoxia-inducible factor-1alpha, an important transcription factor of nickel response, was not required for the cyclin D1 or cyclin E induction. The role of p53 in nickel-induced G(2)/M arrest was excluded, respecting that its protein level, ser(15) phosphorylation, and transcriptional activity were not changed in nickel response. Further study revealed that cyclin A was not activated in nickel response, and cyclin B1, which not only promotes G(2)/M transition but also prevents M-phase exit of cells if not degraded in time, was up-regulated by nickel through a manner independent of hypoxia-inducible factor. More importantly, our results verified that overexpressed cyclin B1, veiling the effect of cyclin D1 or cyclin E, mediated nickel-caused M-phase blockage and cell growth inhibition, which may render pulmonary cells more sensitive to DNA damage and facilitates cancer initiation. These results will not only deepen our understanding of the molecular mechanism involved in nickel carcinogenecity, but also lead to the further study on chemoprevention of nickel-associated human cancer.
Ding
Jin
J
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
He
Guoping
G
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Gong
Wenfeng
W
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Wen
Wen
W
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Sun
Wen
W
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Ning
Beifang
B
Department of Gastroenterology of Changzheng hospital, Second Military Medical University, Shanghai, China.
Huang
Shanna
S
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Wu
Kun
K
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Huang
Chuanshu
C
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
Wu
Mengchao
M
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
Xie
Weifen
W
Department of Gastroenterology of Changzheng hospital, Second Military Medical University, Shanghai, China.
Wang
Hongyang
H
The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002273:Carcinogens; D016213:Cyclins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; C022838:nickel chloride; D009532:Nickel