Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 1...Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein degradation, it was hypothesized that loss-of-function mutations of SPOP led to accumulation of SPOP substrates that enhance androgen receptor activity and facilitate prostate cancer formation. SPOP substrates could thus be potential targets for treatment of androgen-sensitive prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1 are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1, by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and 22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib. LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most sensitive. SRC-3 protein decreased when LNCaP cells were treated with lestaurtinib;whereas PRK-1 increased in nucleus after lestaurtinib treatment. These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to induced cell death in androgen-sensitive prostate cancer, and could be a useful agent for future development for prostate cancer with SPOP mutations.展开更多
在胚胎发育中发挥重要作用的许多基因,其异常表达或突变常与疾病密切相关,斑点型BTB/POZ蛋白(speckle type BTB/POZ protein,SPOP)是其中之一。SPOP是E3泛素连接酶接头蛋白质,主要由MATH、BTB和BACK结构域构成,其功能正常发挥依赖于多...在胚胎发育中发挥重要作用的许多基因,其异常表达或突变常与疾病密切相关,斑点型BTB/POZ蛋白(speckle type BTB/POZ protein,SPOP)是其中之一。SPOP是E3泛素连接酶接头蛋白质,主要由MATH、BTB和BACK结构域构成,其功能正常发挥依赖于多个结构域各自不同的作用。SPOP主要通过泛素-蛋白酶体途径促进其靶蛋白质的降解来发挥作用。目前发现,SPOP底物蛋白质有30多种,其中大部分与前列腺癌、子宫内膜癌和肾癌的发生发展相关。SPOP在机体发育过程中也发挥重要作用,缺失或者突变SPOP导致小鼠出生后死亡。SPOP新生突变导致儿童神经发育障碍。SPOP调控机体发育也主要通过调控靶蛋白质降解来实现,包括作用于Gli2/3、PDX1、NANOG和SENP7等靶蛋白质来调控神经、骨骼和胰腺的发育以及衰老等过程。另有研究发现,SPOP与靶蛋白质会共定位到核斑(nuclear speckles)等无膜细胞器中,促进靶蛋白质的泛素化降解,并且SPOP寡聚体的形成以及其与底物多价互作引发的液-液相分离(liquid-liquid phase separation,LLPS)也在其中发挥了重要作用。SPOP寡聚化缺陷的BTB突变或BACK突变,可导致SPOP无法发生液-液相分离并定位于无膜细胞器。本文综合了最新研究进展,详细探讨了SPOP在机体发育过程中的重要作用。展开更多
文摘子宫内膜癌(endometrial cancer,EC)是最常见的妇科恶性肿瘤,其发病率逐年上升.近年来,随着靶向治疗在临床上的广泛应用,探索与研究新靶点成为实现子宫内膜癌精准治疗的重要一环.越来越多的研究发现,E3泛素连接酶斑点型锌指结构蛋白(speckle-type POZ protein,SPOP)对子宫内膜癌的发生发展起到了重要的抑制作用.本文将介绍泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)SPOP的结构、功能,探讨调控和影响SPOP的因素以及SPOP在子宫内膜癌中的突变情况和相关底物.重点围绕SPOP的下游三条信号通路:雌激素受体α(estrogen receptor-α,ERα)介导的信号通路、溴结构域和端外蛋白(bromodomain and extraterminal protein,BET)通路及锌指和BTB结构域蛋白3(zinc finger and BTB domain-containing protein 3,ZBTB3)通路,对它们抑制子宫内膜癌发生发展的分子机制进行总结,以期为SPOP作为新的子宫内膜癌治疗靶点提供理论基础.
文摘Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein degradation, it was hypothesized that loss-of-function mutations of SPOP led to accumulation of SPOP substrates that enhance androgen receptor activity and facilitate prostate cancer formation. SPOP substrates could thus be potential targets for treatment of androgen-sensitive prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1 are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1, by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and 22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib. LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most sensitive. SRC-3 protein decreased when LNCaP cells were treated with lestaurtinib;whereas PRK-1 increased in nucleus after lestaurtinib treatment. These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to induced cell death in androgen-sensitive prostate cancer, and could be a useful agent for future development for prostate cancer with SPOP mutations.
