BMP4 (bone morphogenetic protein 4) is a multifunctional cytokine known to exert its biological effects through a variety of signalling pathways. The diverse function of BMP4 appears to be due to multiple pathways activated by BMP4 itself. Our previous studies have demonstrated that BMP4 is able to drive lung cancer cells into a process of premature senescence; however, the signalling pathways, as well their interplays and roles associated with this process, are not well understood. To address these questions, in the present study we investigated the signalling and molecular mechanisms underlying the BMP4-induced senescence, and our data demonstrated that p38 MAPK (mitogen-activated protein kinase) and Smad pathways were necessary for this process. Meanwhile, the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which is required for senescence, was not activated by BMP4 in the lung cancer cell line NCI-H460. We also showed that the BMP4-responsive R-Smads (receptor-regulated Smads), i.e. Smad1 and Smad5, were necessary for the up-regulation of p16INK4a and p21WAF1/cip1 and for the induction of premature senescence. Furthermore, we found that activation of the p38 MAPK pathway by BMP4 was essential for the full activation of transcription potential of Smad1/5. Overall, the results of the present study implicate a complex co-operation between p38 MAPK and Smad pathways in BMP4-mediated premature senescence.
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Research Article|
December 22 2010
Role of p38 MAPK pathway in BMP4-mediated Smad-dependent premature senescence in lung cancer cells
Dongmei Su
;
Dongmei Su
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China
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Xiue Peng
;
Xiue Peng
†
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, People's Republic of China
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Shan Zhu
;
Shan Zhu
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China
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Ying Huang
;
Ying Huang
†
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, People's Republic of China
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Zhixiong Dong
;
Zhixiong Dong
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China
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Yu Zhang
;
Yu Zhang
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China
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Jianchao Zhang
;
Jianchao Zhang
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China
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Qian Liang
;
Qian Liang
†
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, People's Republic of China
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Jun Lu
;
Jun Lu
1
†
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, People's Republic of China1
Correspondence may be addressed to either of these authors (email luj809@nenu.edu.cn or huangbq705@nenu.edu.cn).
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Baiqu Huang
Baiqu Huang
1
*
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, People's Republic of China1
Correspondence may be addressed to either of these authors (email luj809@nenu.edu.cn or huangbq705@nenu.edu.cn).
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Biochem J (2011) 433 (2): 333-343.
Article history
Received:
April 23 2010
Revision Received:
November 03 2010
Accepted:
November 04 2010
Accepted Manuscript online:
November 04 2010
Citation
Dongmei Su, Xiue Peng, Shan Zhu, Ying Huang, Zhixiong Dong, Yu Zhang, Jianchao Zhang, Qian Liang, Jun Lu, Baiqu Huang; Role of p38 MAPK pathway in BMP4-mediated Smad-dependent premature senescence in lung cancer cells. Biochem J 15 January 2011; 433 (2): 333–343. doi: https://doi.org/10.1042/BJ20100404
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