Role of p38 MAPK pathway in BMP4-mediated Smad-dependent premature senescence in lung cancer cells.
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 p16(INK)⁴(a) and p21(WAF)¹(/cip)¹ 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.
The Institute of Genetics and Cytology, Northeast Normal University, Changchun, People's Republic of China.
Dongmei
D
Su
Xiue
X
Peng
Shan
S
Zhu
Ying
Y
Huang
Zhixiong
Z
Dong
Yu
Y
Zhang
Jianchao
J
Zhang
Qian
Q
Liang
Jun
J
Lu
Baiqu
B
Huang
D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases