〔Abstract〕 Objective To investigate the effect and mechanism of RasGAP binding protein 2(G3 BP2) on senescence of colon cancer cells. Methods The G3 BP2-specific siRNA(siG3 BP2#1 and siG3 BP2#2) and G3 BP2 overexpressing plasmids were used to construct G3 BP2 knockdown and overexpression colon cancer cell models, and the expression of G3 BP2 was detected by Western blot. Cell proliferation was detected by CCK8 assay. The proportion of senescent cells was detected by β-galactosidase staining, the protein levels of p53 and p21 were determined by Western blot. p53 siRNA or p53 overexpressing plasmid was used to conduct repression experiments. The cell proliferation ability was detected by the above methods. Results The siG3 BP2#1和siG3 BP2#2 could down-regulate the expression of G3 BP2 while G3 BP2 overexpressing plasmid could up-regulate the expression of G3 BP2. G3 BP2 knockdown significantly decreased the proliferation of colon cancer cells and increased the proportion of senescent cells from(32.00±5.10)% to(57.33±3.68)% and(56.00±6.68)%(P<0.05). After transfected with G3 BP2 overexpressing plasmid, the proliferation of colon cancer cells increased, and the proportion of senescent cells decreased from(35.33±2.87)% to(25.00±2.94)%(P<0.05). Compared with the control group, the levels of p53 and p21 protein in G3 BP2 knockdown cells were significantly increasedwhile the expression of p53 and p21 protein in G3 BP2 overexpressed cells was significantly decreased(P<0.05); low expression of p53 reversed inhibition of tumor proliferation and promoted cellular senescence induced by down-regulation of G3 BP2, while overexpression of p53 reversed the effect of G3 BP2 up-regulation on promoting tumor proliferation and inhibiting cellular senescence. Conclusion G3 BP2 promotes cell senescence by inhibiting p53/p21 signaling pathway in colon cancer, which may provide the potential target for tumor therapy.