野生型p53基因的抑癌活性在肿瘤患者中常存在被抑制的现象。最新研究发现,p53的抑癌活性由p53凋亡刺激蛋白(apoptosis-stimulating protein of p53,ASPP)家族调控。该家族包含3个成员:p53凋亡抑制蛋白(inhibitory member of the apoptos...野生型p53基因的抑癌活性在肿瘤患者中常存在被抑制的现象。最新研究发现,p53的抑癌活性由p53凋亡刺激蛋白(apoptosis-stimulating protein of p53,ASPP)家族调控。该家族包含3个成员:p53凋亡抑制蛋白(inhibitory member of the apoptosis-stimulating protein of p53,iASPP)、p53 ASPP1和p53 ASPP2。大量研究表明,iASPP是抑制p53活性和功能的重要因素,其表达和功能与肿瘤患者的临床表现、治疗效果和预后密切相关,在多种肿瘤的发生发展过程中发挥着重要的促进作用。通过本篇综述,作者期望对iASPP的特性和功能有较全面的了解,为今后以iASPP为靶点的抗肿瘤治疗提供新的思路。展开更多
Background:Inhibitor of apoptosis-stimulating protein of p53(iASPP)is an evolutionarily conserved p53 inhibitor.Mechanistically,iASPP can accelerate tumorigenesis by inhibiting the transactivation function of p53.Targ...Background:Inhibitor of apoptosis-stimulating protein of p53(iASPP)is an evolutionarily conserved p53 inhibitor.Mechanistically,iASPP can accelerate tumorigenesis by inhibiting the transactivation function of p53.Targeting the interaction between iASPP and p53 may be a potential therapy for restoring the activity of p53 in tumors.Methods:We constructed an iASPP-derived peptide,called A8,that was derived from the C-terminus of iASPP.Here,we transfected A8 into two wildtype(WT)p53 cell lines,U2OS and A549,and then determined the number of apoptotic cells.The mechanism by which A8 affected apoptosis was further examined by immunoprecipitation(IP),Dual-Luciferase reporter assays,and chromatin IP assays.Real-time polymerase chain reaction and western blots were also used to examine the expression levels of apoptosis-related factors.Results:Our data demonstrate that A8 can increase apoptosis rates in WT p53 cell lines.Functional analysis suggested that A8 restored the transcriptional function and DNA binding activities of p53 toward the Bax and PUMA gene promoters.Moreover,A8 reduced cell proliferation and inhibited tumor growth in xenograft nude mice.Conclusions:These data provide a new approach for restoring the tumor suppressor function of p53 in cancer cells that express WT p53 and therefore may serve as a novel cancer treatment strategy.展开更多
文摘野生型p53基因的抑癌活性在肿瘤患者中常存在被抑制的现象。最新研究发现,p53的抑癌活性由p53凋亡刺激蛋白(apoptosis-stimulating protein of p53,ASPP)家族调控。该家族包含3个成员:p53凋亡抑制蛋白(inhibitory member of the apoptosis-stimulating protein of p53,iASPP)、p53 ASPP1和p53 ASPP2。大量研究表明,iASPP是抑制p53活性和功能的重要因素,其表达和功能与肿瘤患者的临床表现、治疗效果和预后密切相关,在多种肿瘤的发生发展过程中发挥着重要的促进作用。通过本篇综述,作者期望对iASPP的特性和功能有较全面的了解,为今后以iASPP为靶点的抗肿瘤治疗提供新的思路。
基金National Natural Science Foundation of China,Grant/Award Number:81602710。
文摘Background:Inhibitor of apoptosis-stimulating protein of p53(iASPP)is an evolutionarily conserved p53 inhibitor.Mechanistically,iASPP can accelerate tumorigenesis by inhibiting the transactivation function of p53.Targeting the interaction between iASPP and p53 may be a potential therapy for restoring the activity of p53 in tumors.Methods:We constructed an iASPP-derived peptide,called A8,that was derived from the C-terminus of iASPP.Here,we transfected A8 into two wildtype(WT)p53 cell lines,U2OS and A549,and then determined the number of apoptotic cells.The mechanism by which A8 affected apoptosis was further examined by immunoprecipitation(IP),Dual-Luciferase reporter assays,and chromatin IP assays.Real-time polymerase chain reaction and western blots were also used to examine the expression levels of apoptosis-related factors.Results:Our data demonstrate that A8 can increase apoptosis rates in WT p53 cell lines.Functional analysis suggested that A8 restored the transcriptional function and DNA binding activities of p53 toward the Bax and PUMA gene promoters.Moreover,A8 reduced cell proliferation and inhibited tumor growth in xenograft nude mice.Conclusions:These data provide a new approach for restoring the tumor suppressor function of p53 in cancer cells that express WT p53 and therefore may serve as a novel cancer treatment strategy.
