The Preliminary Study On The Function Of PP2A Complex In Cellular Senescence Induced By Ras

In recent years,oncogene-induced senescence(OIS)has been of interest since it is considered as a hot spot in cancer research areas.OIS occurs at the early stage of tumoregenesis,which limits the cell proliferation caused by mutations and ectopic expression of oncogenes.Given that the OIS maintains tumors in non-invasive precancerous conditions,it is thought to be an innate protective anti-cancer mechanism.Studies have shown that the activation of oncogene Ras can induce OIS.Once the mechanism of senescence is defective,Ras may stimulate infinite proliferation of cells leading to malignant tumors.Protein phosphatase 2A(PP2A)refers to an important serine/threonine phosphatase.The mutations in PP2 A were detected in difference types of cancers.Recent studies have indicated that PP2A-B56? complex can inhibit tumoregenesis,whereas the mechanism remains elusive.Moreover,the simian virus 40 small T(SV40 ST)can replace B56? subunit in PP2 A complex that inhibits PP2 A signaling pathway.SV40 ST promises thus to be a potential tool in the research for PP2 A signaling pathway.In this study,we have first constructed lentivirus expressing SV40 ST.We found that overexpression of SV40 ST inhibited the Ras-induced phosphorylation of ERK,and significantly decreased the accumulation of DNA damage marker ? H2 A.X and 53BP1 that inhibited Ras-induced cellular senescence.We further found that PP2A-B56? knockdown by shRNA could mimic the inhibitory effect of SV40 ST in Ras-induced cellualr senescence.Together with the recent data on the interaction of SV40 ST and PP2 A,we propose that SV40 ST inhibits Ras-induced cellualr senescence through PP2A-B56?.In addition,PP2A-B56? knockdown inhibits Ras/Raf/Mek/ERK pathway and the accumulation of DNA damage protein markers.Overexpression of P2A-B56? neither impacts DNA damage nor induces the senescent phenotype of IMR90 cells.Taken together,we propose that PP2 A relieves the negative feedback in Ras signaling pathway and thus maintains the sustained activation of Ras/Raf/Mek/ERK pathway.But PP2 A can not stimulate Ras/Raf/Mek/ERK pathway independently to induce cellular senescence.