The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At...The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.展开更多
目的:研究P38丝裂原活化蛋白激酶(P38mitogen-activated protein kinases,P38MAPK)通路在骨形态发生蛋白9(Bonemorphogenetic protein 9,BMP9)诱导C3H10T1/2干细胞向心肌样细胞分化中的作用。方法:免疫印迹检测经pAdEasyBMP9诱导24 h的C...目的:研究P38丝裂原活化蛋白激酶(P38mitogen-activated protein kinases,P38MAPK)通路在骨形态发生蛋白9(Bonemorphogenetic protein 9,BMP9)诱导C3H10T1/2干细胞向心肌样细胞分化中的作用。方法:免疫印迹检测经pAdEasyBMP9诱导24 h的C3H10T1/2干细胞磷酸化P38MAPK和P38MAPK表达水平,免疫荧光定位磷酸化P38MAPK;SB203580抑制C3H10T1/2干细胞磷酸化P38MAPK活性,pAdEasyBMP9诱导21 d时免疫印迹检测心肌特异性蛋白CX43、cTnT表达,免疫荧光检测心肌特异性蛋白cTnT、α-MHC表达,RT-qPCR检测心肌特异性基因GATA4、MEF2C表达。结果:pAdEasyBMP9促进磷酸化P38MAPK表达增高,却不影响P38MAPK表达水平;磷酸化P38MAPK有表达于胞浆和胞核、仅表达于胞核的不同状态。SB203580可显著性地抑制由pAdEasyBMP9诱导的C3H10T1/2干细胞CX43、cTnT、α-MHC、GATA4、MEF2C表达。结论:pAdEasyBMP9诱导C3H10T1/2干细胞能激活P38MAPK通路,并促进其向心肌样细胞分化。展开更多
基金funded by the Ministry of Science and Higher Education of the Russian Federation(Grant No.075-15-2020-795 of 29.09.2020,unique project ID:RF-190220X0027).
文摘The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.
文摘目的:研究P38丝裂原活化蛋白激酶(P38mitogen-activated protein kinases,P38MAPK)通路在骨形态发生蛋白9(Bonemorphogenetic protein 9,BMP9)诱导C3H10T1/2干细胞向心肌样细胞分化中的作用。方法:免疫印迹检测经pAdEasyBMP9诱导24 h的C3H10T1/2干细胞磷酸化P38MAPK和P38MAPK表达水平,免疫荧光定位磷酸化P38MAPK;SB203580抑制C3H10T1/2干细胞磷酸化P38MAPK活性,pAdEasyBMP9诱导21 d时免疫印迹检测心肌特异性蛋白CX43、cTnT表达,免疫荧光检测心肌特异性蛋白cTnT、α-MHC表达,RT-qPCR检测心肌特异性基因GATA4、MEF2C表达。结果:pAdEasyBMP9促进磷酸化P38MAPK表达增高,却不影响P38MAPK表达水平;磷酸化P38MAPK有表达于胞浆和胞核、仅表达于胞核的不同状态。SB203580可显著性地抑制由pAdEasyBMP9诱导的C3H10T1/2干细胞CX43、cTnT、α-MHC、GATA4、MEF2C表达。结论:pAdEasyBMP9诱导C3H10T1/2干细胞能激活P38MAPK通路,并促进其向心肌样细胞分化。
