The Crosstalking Of P38 MAPK And Smad Pathway In BMP4 Mediated Premature Senescence In Lung Cancer Cells

Our previous study demonstrated that p38 MAPK pathway and Smad pathway plays an important role in BMP4-mediated premature senescence in lung caner cells. Smad1 and Smad5 can up-regulate p16 and p21 which are downstream of BMP4, whereas SB203580, the inhibitor of p38, can down-regulate p16 and p21 expression. However, the specific molecular mechanism is unclear. Our experiments confirmed that p38 MAPK pathway was not involved in mediating nuclear translocation of Smad proteins. Luciferase reporter assays showed that the promoter activity of p16 and p21 was up-regulated upon the co-expression of Sp1 with Smad1 and Smad5. Co-immunoprecipitation assay showed that the association between Sp1 and Smad1 or Smad5 was greatly increased when BMP4 overexpressed, but decreased again when cells were treated with SB203580.In conclusion, our experiments confirmed that the p38 MAPK may promote the expression of p16 and p21 by mediating the cooperation of its downstream factors Sp1 and Smad1/5. This work provides an important experimental basis for clarifying the molecular mechanism of BMP4-mediated premature senescence in lung cancer cells.