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
目的探讨T细胞淋巴瘤p53突变和其周围微卫星DNA的改变及两者的关系，以进一步研究T细胞淋巴瘤的分子遗传学发病机制。方法采用PCR、PCR-SSCP技术观察38例T细胞淋巴瘤的肿瘤组织及其肿瘤旁淋巴组织或同一病例的反应性增生淋巴结组织进行...目的探讨T细胞淋巴瘤p53突变和其周围微卫星DNA的改变及两者的关系，以进一步研究T细胞淋巴瘤的分子遗传学发病机制。方法采用PCR、PCR-SSCP技术观察38例T细胞淋巴瘤的肿瘤组织及其肿瘤旁淋巴组织或同一病例的反应性增生淋巴结组织进行p53基因外显子5-8的点突变研究和p53周围4个微卫星位点D17S945、D17S938、D17S947、D17S926的微卫星（microsatellite，MS）改变：微卫星不稳定性（microsatellite instability，MSI）和杂合性缺失（loss of heterozygosity，LOH）分析。结果p53基因外显子5-8总突变率为39．47％（15／38）。微卫星改变的阳性率为23．68％（9／38），LOH为7．89％（3／38）。各位点MSI、LOH频率介于2．86％-18．42％和0-5．26％。微卫星改变阳性肿瘤的p53突变率为55．56％（5／9），阴性者为34．48％（10／29）（P〉0．05）。D17S926和D17S947位点LOH阳性组与阴性组的p53突变率分别为100％、36．11％（P〉0．05）。结论T细胞淋巴瘤中存在微卫星改变和p53基因突变，两者发生无明显关系。但微卫星改变阳性的肿瘤，p53突变倾向于高发。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.
文摘目的探讨T细胞淋巴瘤p53突变和其周围微卫星DNA的改变及两者的关系，以进一步研究T细胞淋巴瘤的分子遗传学发病机制。方法采用PCR、PCR-SSCP技术观察38例T细胞淋巴瘤的肿瘤组织及其肿瘤旁淋巴组织或同一病例的反应性增生淋巴结组织进行p53基因外显子5-8的点突变研究和p53周围4个微卫星位点D17S945、D17S938、D17S947、D17S926的微卫星（microsatellite，MS）改变：微卫星不稳定性（microsatellite instability，MSI）和杂合性缺失（loss of heterozygosity，LOH）分析。结果p53基因外显子5-8总突变率为39．47％（15／38）。微卫星改变的阳性率为23．68％（9／38），LOH为7．89％（3／38）。各位点MSI、LOH频率介于2．86％-18．42％和0-5．26％。微卫星改变阳性肿瘤的p53突变率为55．56％（5／9），阴性者为34．48％（10／29）（P〉0．05）。D17S926和D17S947位点LOH阳性组与阴性组的p53突变率分别为100％、36．11％（P〉0．05）。结论T细胞淋巴瘤中存在微卫星改变和p53基因突变，两者发生无明显关系。但微卫星改变阳性的肿瘤，p53突变倾向于高发。
