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LXXLL模体最先在核受体辅激活因子CBP/p300和类固醇受体辅激活因子1(steroid receptor coactivator 1,SRC1)蛋白序列中发现,随后在甲基化CpG结合核酸内切酶1(methyl-CpG-binding endonuclease 1,MED1)、SRC/p160和过氧化物酶体增殖物激活受体γ辅激活因子1(peroxisome proliferator-activated receptor γ coactivator-1,PGC-1)等许多其他核受体辅调节因子的蛋白序列中也被广泛地发现[7]。这一研究主要是通过酵母双杂交系统(yeast two-hybrid system)、免疫共沉淀(coimmunoprecipitation)、体外报告谷胱甘肽S-转移酶沉降试验以及基因点突变(gene mutation)等技术手段完成的(图 1)。Zhang等[8]通过这类方法研究表明,位于辅调节因子SRC1和PGC-1蛋白上的LXXLL模体在调节它们与ER的相互作用中是不可或缺的。随着以上实验技术的完善和研究的深入,含有LXXLL模体的ER新的辅调节因子不断地被发现,表 1总结了目前为止已发现的含有LXXLL模体的ER辅调节因子及其功能和在相关疾病中的作用。
基因 人类基因编号 LXXLL序列(氨基酸位点) 在核受体中的作用 蛋白质功能 在疾病发生中的作用 发现时间 参考文献 CBP 1387 QLSELLRG(68-75)
QLVLLLHA(356-363)辅激活因子 组蛋白乙酰化,与SRC家族相互作用 在亨廷顿舞蹈症、白血病、脊延髓肌肉萎缩中异常表达 1996 [9] p300 2033 KLSELLRS(80-87)
QLVLLLHA(341-348)
ALQNLLRT(2050-1057)辅激活因子 组蛋白乙酰化,与SRC家族相互作用 在胃肠道肿瘤中杂合性缺失、白血病中形成异常Moz融合蛋白,突变可引起多发性肿瘤 1996 [10] SRC-1/NCOA1 8648 KLVQLLTT(252-260)
ILHRLLQE(309-318)
LLRYLLDK(368-375)
QLDELLCP(532-539)
LLQQLLTE(1054-1061)辅激活因子 组蛋白乙酰化,参与信号转导和转录激活子家族介导的转录激活 在乳腺癌、前列腺癌、子宫内膜癌中过量表达,突变可引起横纹肌肉瘤 1997 [7] SRC2/GRIP1/TIF2 10499 KLLQLLTT(640-647)
ILHRLLQD(689-696)
LLRYLLDK(744-751)
QLGRLLPN(877-884)辅激活因子 组蛋白乙酰化、与辅激活因子相关精氨酸甲基转移酶1和EP300/p300等形成复合物 在乳腺癌、脑部肿瘤中过量表达,在白血病中形成Moz-tif融合蛋白 1998 [11-13] pCAF 8850 YLFGLLRK(189-196) 辅激活因子 组蛋白乙酰化,与雌激素受体的DNA结合区域相互作用 缺失可导致直结肠癌 1998 [14-15] TRAP220/MED1/DRIP205/PIBP 5469 ILTSLLQI(603-610)
MLMNLLKD(644-651)辅激活因子 中介体,与众多MEDs形成调节复合体 缺失可导致Williams综合症 1998 [16-17] SRC3/AIB1/NCOA3 8202 KLVQLLTT(621-628)
ILHRLLQD(684-691)
LLRYLLDK(735-742)辅激活因子 组蛋白乙酰化,可与CBP/p300形成激活复合物 基因变异可导致乳腺癌、卵巢癌,在直结肠癌中过量表达 1998 [18-19] NRIF3/ITGB3BP 23421 FLKALLN(8-15)
KLDGLLEE(171-177)辅激活因子 与蛋氨酸腺苷转移酶1相互作用,调节乳腺癌细胞对雌激素的敏感程度 有待研究 1999 [20-21] ASC-1 9325 RLAVLLPG(160-167) 辅激活因子 招募组蛋白乙酰化酶,与CBP/p00、SRC-1相互作用,在核转录因子κB、激活蛋白1的转录激活中发挥重要作用 有待研究 1999 [22] LZIP/CREB3 17039 DLLALLEE(12-19)
DLLSLLSP(52-59)辅激活因子 可以与环磷酸腺苷反应元件结合,调控细胞增殖,可正向调控核转录因子κB通路,与疱疹病毒VP16感染有联系 增加白血病的迁移 2000 [23] PGC-1 10891 LLKKLLLA(143-147) 辅激活因子 参与mRNA的剪切,正向调节组蛋白乙酰化,并在能量代谢和脂肪细胞分化中具有重要作用 表达水平与乳腺癌的病死率成反比,且在心血管和糖尿病等疾病中异常表达 2000 [24-25] TRBP/RAP250/ASC-2 23054 LLVNLLQS(886-893)
LLSQLLDN(1490-1497)辅激活因子 招募组蛋白乙酰化酶,并参与DNA复制和损伤修复 突变可导致乳腺癌 2000 [26-27] DRIP150/MED14 9282 ALNILLLP(69-76)
VLTDLLPR(1181-1188)辅激活因子 中介体,与众多MEDs形成调节复合体,参与RNA聚合酶II的转录功能 有待研究 2000 [28] CIA 57727 SLINLLAD(386-393) 辅激活因子/辅抑制因子 具备氨酰基-转运RNA连接酶功能,可以与ATP结合,且与雌激素受体的结合不依赖于转录激活区2 有待研究 2001 [29] PNRC2 55629 QLKTLLKV(171-177) 辅激活因子 参与无意义密码子介导的mRNA降解 有待研究 2001 [30] TIP60 10524 MLKRLLRI(492-499) 辅激活因子 组蛋白乙酰化酶复合体NuA4的催化成分,且可以直接使毛细血管扩张共济失调突变基因乙酰化,在细胞修复中发挥作用 有待研究 2001 [31] PERC/PGC-1 133522 LLQKLLLA(155-162)
ILRELLAQ(342-349)
ILRELLAQ(342-349)辅激活因子 转录调节复合体成分之一,可以与RNA结合,参与能量代谢调节和脂肪细胞分化 基因突变可导致乳腺癌、肥胖、2型糖尿病,在甲状腺嗜酸细胞瘤中过量表达 2002 [32-33] TRAP100/MED24 9862 SLDLLLAA(447-454)
ILPGLLTD(787-794)辅激活因子 中介体,与众多MEDs形成调节复合体,参与RNA聚合酶II的转录功能 在乳腺癌中过量表达 2002 [34-35] MNAR/PELP1 27043 CLLSLLYG(28-35)
VLRDLLRY(72-79)
HLPGLLTS(94-101)
LLTSLLGL(98-105)
ELHSLLAS(181-188)
SLHTLLGA(188-195)
PLRLLLLP(281-289)
LLTHLLSD(376-383)
ELYCLLLA(496-503)
LLALLLAP(501-508)辅激活因子 可以与生长因子信号通路中组分表皮生长因子受体、肝细胞生长因子调节酪氨酸激酶作用物等相互作用,通过视网膜母细胞瘤抑制蛋白1在雌激素介导的细胞周期进展中发挥作用,并且同SRC、磷脂酰肌醇3激酶、信号转导和转录激活子3等相互作用 细胞质内浓度增高时可以导致乳腺癌,过量表达可导致子宫内膜癌、涎腺导管癌等 2004 [36-37] MLL2 8055 RLRELLIR(2685-2691)
HLDDLLNG(3037-3043)
QLQALLMQ(4221-4227)
PLOGLLGC(4252-4258)
LLQKLLRA(4187-4194)
RLRLLLTT(4714-4721)辅激活因子 具有甲基转移酶的功能,可以使组蛋白H3的Lys-3甲基化,被雌激素受体1所招募激活雌激素受体功能 缺失可导致Kabuki综合征,在乳腺癌中过量表达 2006 [38-39] CCDC62/ERAP75 84600 KLQRLLAE(633-640)
ELSTLLPI(649-656)辅激活因子 可以增强雌激素介导的cyclinD1的表达和促进细胞的生长 在前列腺癌细胞中广泛表达 2009 [40] ACTN-4 43707 KLMLLLEV(83-90) 辅激活因子 肌动蛋白结合蛋白,苯丙胺调节转录因子复合物的组成部分 突变可导致1型局灶节段性肾小球硬化 2011 [41] DAX-1 190 ILYSLLTS(145-152) 辅抑制因子 可与核受体亚家族5-A组-成员1蛋白和核受体亚家族0-B组-成员2蛋白形成多异聚体,并招募其他辅抑制子,在肾上腺激素轴的发育中具有重要作用 缺失可导致X染色体偶联的阿狄森氏病和剂量敏感性性反转 2000 [8] SHP-1 5777 ILYALLTS(19-26) 辅抑制因子 可以与DNA直接结合 突变与早发性肥胖有关 2000 [8] RIP140 8204 YLEGLLMH(20-27)
LLASLLQS(132-139)
HLKTLLKK(184-191)
QLALLLSS(265-272)
LLLHLLKS(379-386)
LLLLLLGH(499-506)
VLQLLLGN(712-719)
LLSRLLRQ(818-825)
VLKQLLLS(935-972)辅抑制因子 招募组蛋白去乙酰化酶1、组蛋白去乙酰化酶3等组蛋白去乙酰化酶,并与核受体辅激活子1形成复合物 突变可导致子宫内膜癌和不孕 2001 [42] R-MGMT 4255 VLWKLLKV(95-105) 辅抑制因子 具有甲基转移酶的活性,在DNA损伤后,可以抑制雌激素受体介导的细胞增殖 基因突变或单倍体可导致膀胱癌和脑部肿瘤,在肺癌中过量表达 2001 [43] LCoR 84458 VLSKLLMA(52-59) 辅抑制因子 可以与DNA直接结合,招募羧基末端结合蛋白1、组蛋白去乙酰化酶3、组蛋白去乙酰化酶6等共同组成转录辅抑制复合物 有待研究 2003 [44] REA 11331 ALKLLLGA(22-29) 辅抑制因子 中介体,招募组蛋白去乙酰化酶 在乳腺癌中低表达 2003 [45] ERR10/NAG7 29931 FLIWLLCW(336-343)
FLPHLLNQ(322-329)辅抑制因子 抑制雌激素受体调c-Jun氨基末端激酶琢的活性/激活蛋白,并上1/金属基质蛋白酶1信号通路 在胃肠肿瘤中高表达,可以增强鼻咽癌的侵袭能力 2004 [46] PROX1 5629 VLRKLLKR(69-76) 辅抑制因子 在机体的神经系统和内脏发育中发挥重要作用 低表达可导致肝癌、胰腺癌等 2006 [47] ERK8 9606 TLDALLPP(264-271)
LLRRLLVF(280-287)辅抑制因子 具备ATP结合活性和苏氨酸/丝氨酸激酶的活性,参与蛋白的磷酸化 有待研究 2011 [48] 注:CBP:CREB结合蛋白;SRC:类固醇受体辅激活因子;SRC-1/NCOA-1:类固醇/核受体辅激活因子1;SRC2/GRIP1:类固醇受体激活子2/糖皮质激素受体作用蛋白1;PCAF:P300/CBP相关因子;TRAP220:甲状腺激素受体相关蛋白220;MED:甲基化CpG结合核酸内切酶;DRIP205:维生素D受体作用蛋白205;PIBP:磷酸肌醇结合蛋白;SRC3/AIB1:类固醇受体辅激活因子3/乳腺癌扩增性抗原1;NCOA3:核受体辅激活子3;NRIF3:核受体作用因子3;ITGB3BP:整合素β3结合蛋白;ASC-1:激活信号辅整合子1;LZIP:亮氨酸拉链转录分子;CREB:环磷酸腺苷反应元件结合蛋白;PGC-1:过氧化物酶体增殖物激活受体γ辅激活因子1;TRBP:反式激活RNA结合蛋白;RAP250:核受体激活蛋白250;DRIP150:维生素D受体作用蛋白150;CIA:非依赖AF-2功能的辅激活因子;PNRC2:脯氨酸富集核受体辅激活因子2;TIP60:1型作用蛋白60;TRAP100:甲状腺激素受体相关蛋白100;PERC:过氧化物酶体增殖物激活受体辅激活因子;MNAR:雌激素受体非基因作用调节因子;PELP1:脯氨酸-谷氨酸-亮氨酸富集蛋白1;MLL2:混合谱系白血病基因编码蛋白2;CCDC 62:螺旋化螺旋结构域蛋白62;ERAP75:雌激素受体相关蛋白75;ACTN-4:辅肌动蛋白4;DAX-1:先天性肾上腺发育不良基因编码蛋白;SHP-1:包含SH-2功能域的蛋白酪氨酸磷酸酶1;RIP140:受体相互作用蛋白140;R-MGMT:DNA修复酶-甲基鸟嘌呤DNA甲基转移酶;LCoR:配体依赖的核受体辅抑制因子;REA:雌激素功能抑制因子;ERR10:雌激素相关受体10;NAG7:N-乙酰-β-D-氨基葡萄糖苷酶7;PROX1:Prospero同源盒基因1;ERK8:细胞外信号调节激酶8。 表 1 含有LXXLL模体的雌激素受体辅调节因子一览表
Table 1. Co-regulators containing LXXLL motif in estrogen receptor signal pathway
值得注意的是,虽然LXXLL模体在ER信号通路转导过程中起着重要作用,但并不代表LXXLL模体仅存在于ER或核受体信号途径中,很多其他蛋白质之间的相互作用也会涉及到LXXLL模体。有研究表明,LXXLL模体参与了慢性淋巴性白血病相关的基因转录沉默过程,且LXXLL模体在这一过程中的作用机制和其在核受体中的作用机制是不相同的[49]。另外,人们发现很多辅激活因子具有双重功能,它们一方面具有LXXLL模体,另一方面也具有结合LXXLL模体的结构域。例如,在核受体辅激活因子1中羧基端的PAS-B片段中就含有可与辅调节因子信号转导和转录激活子6中的LXXLL模体结合的区域,它们间的相互作用在白细胞介素4的功能中是不可缺少的[50]。最后,我们也应注意到很多ER辅调节因子虽然含有LXXLL模体,但其并不依赖LXXLL模体与ER的LBD结合[45, 49-51]。以上研究结果说明了LXXLL模体在细胞蛋白质-蛋白质相互作用中普遍存在,并且参与调节的过程十分复杂。
LXXLL模体在雌激素受体信号通路中的作用及应用价值
Role of LXXLL motif in modulation of estrogen receptor signaling and its potential application
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摘要: 雌激素受体是核受体超家族中重要的一员,其与雌激素的结合在人类组织器官发育、新陈代谢以及许多疾病的发生和发展中起着重要的作用。协同调节因子是雌激素-雌激素受体信号转录传导途径中的一类重要调节分子,它们可以与雌激素受体直接结合,并作为协同激活因子上调或作为协同抑制因子降低雌激素受体的基因转录功能。蛋白分子结构分析发现,在协同调节因子与雌激素受体的相互作用中,其蛋白序列中含有的一段非常保守的富含亮氨酸的螺旋序列LXXLL模序(L指亮氨酸、X指任意氨基酸)扮演着重要角色,并在辅调节因子,特别是在协同激活因子中广泛地存在。深入研究LXXLL模序与雌激素受体相互作用的分子机制不仅有助于对LXXLL模序在雌激素受体-辅助调节因子蛋白之间相互作用中地位的理解,也为针对LXXLL模体与核受体的作用位点设计新的靶向药物奠定了基础。因此,该文简述了LXXLL模序在雌激素受体协同调节因子中存在的广泛性、LXXLL模序与雌激素受体相互作用的机制以及其在新药设计上的应用等相关方面的研究进展。
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关键词:
- 受体,雌激素 /
- 协同调节因子 /
- LXXLL模序 /
- 共激活因子结合抑制剂 /
- 模拟肽
Abstract: Estrogen receptor(ER), one member of the nuclear receptor superfamily, via binding to estrogen, plays important roles in development and metabolism of human tissues and organs as well as a number of diseases, such as cancer, obesity, diabetes and osteoporosis. Co-regulators, one important kind of factors in the ER transcriptional signaling, increase(as co-activators) or reduce(as co-repressors)ER-mediated transcriptional activity via direct and indirect binding to ER. Increasing evidence has revealed that a short α-helical sequence LXXLL motif(where L is leucine, X is any amino acid), widely present in many co-regulators, especially co-activators, plays an essential or necessary role in co-regulator interaction with ER. To explore the involved mechanism(s) will be helpful in understanding the critical role of LXXLL motif in the interaction of co-regulators and ER. This review briefly describes the potential roles of LXXLL motif in the involvement of ER co-regulators in modulation of ER signaling and underlying mechanisms as well as current progress in developing pharmaceutical agents that modulate ER-coregulator interaction via specifically targeting LXXLL motifs in therapy of hormone-associated cancers.-
Key words:
- Receptors, estrogen /
- Co-regulators /
- LXXLL motif /
- Co-activator binding inhibitors /
- Mimetic Peptide
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表 1 含有LXXLL模体的雌激素受体辅调节因子一览表
Table 1. Co-regulators containing LXXLL motif in estrogen receptor signal pathway
基因 人类基因编号 LXXLL序列(氨基酸位点) 在核受体中的作用 蛋白质功能 在疾病发生中的作用 发现时间 参考文献 CBP 1387 QLSELLRG(68-75)
QLVLLLHA(356-363)辅激活因子 组蛋白乙酰化,与SRC家族相互作用 在亨廷顿舞蹈症、白血病、脊延髓肌肉萎缩中异常表达 1996 [9] p300 2033 KLSELLRS(80-87)
QLVLLLHA(341-348)
ALQNLLRT(2050-1057)辅激活因子 组蛋白乙酰化,与SRC家族相互作用 在胃肠道肿瘤中杂合性缺失、白血病中形成异常Moz融合蛋白,突变可引起多发性肿瘤 1996 [10] SRC-1/NCOA1 8648 KLVQLLTT(252-260)
ILHRLLQE(309-318)
LLRYLLDK(368-375)
QLDELLCP(532-539)
LLQQLLTE(1054-1061)辅激活因子 组蛋白乙酰化,参与信号转导和转录激活子家族介导的转录激活 在乳腺癌、前列腺癌、子宫内膜癌中过量表达,突变可引起横纹肌肉瘤 1997 [7] SRC2/GRIP1/TIF2 10499 KLLQLLTT(640-647)
ILHRLLQD(689-696)
LLRYLLDK(744-751)
QLGRLLPN(877-884)辅激活因子 组蛋白乙酰化、与辅激活因子相关精氨酸甲基转移酶1和EP300/p300等形成复合物 在乳腺癌、脑部肿瘤中过量表达,在白血病中形成Moz-tif融合蛋白 1998 [11-13] pCAF 8850 YLFGLLRK(189-196) 辅激活因子 组蛋白乙酰化,与雌激素受体的DNA结合区域相互作用 缺失可导致直结肠癌 1998 [14-15] TRAP220/MED1/DRIP205/PIBP 5469 ILTSLLQI(603-610)
MLMNLLKD(644-651)辅激活因子 中介体,与众多MEDs形成调节复合体 缺失可导致Williams综合症 1998 [16-17] SRC3/AIB1/NCOA3 8202 KLVQLLTT(621-628)
ILHRLLQD(684-691)
LLRYLLDK(735-742)辅激活因子 组蛋白乙酰化,可与CBP/p300形成激活复合物 基因变异可导致乳腺癌、卵巢癌,在直结肠癌中过量表达 1998 [18-19] NRIF3/ITGB3BP 23421 FLKALLN(8-15)
KLDGLLEE(171-177)辅激活因子 与蛋氨酸腺苷转移酶1相互作用,调节乳腺癌细胞对雌激素的敏感程度 有待研究 1999 [20-21] ASC-1 9325 RLAVLLPG(160-167) 辅激活因子 招募组蛋白乙酰化酶,与CBP/p00、SRC-1相互作用,在核转录因子κB、激活蛋白1的转录激活中发挥重要作用 有待研究 1999 [22] LZIP/CREB3 17039 DLLALLEE(12-19)
DLLSLLSP(52-59)辅激活因子 可以与环磷酸腺苷反应元件结合,调控细胞增殖,可正向调控核转录因子κB通路,与疱疹病毒VP16感染有联系 增加白血病的迁移 2000 [23] PGC-1 10891 LLKKLLLA(143-147) 辅激活因子 参与mRNA的剪切,正向调节组蛋白乙酰化,并在能量代谢和脂肪细胞分化中具有重要作用 表达水平与乳腺癌的病死率成反比,且在心血管和糖尿病等疾病中异常表达 2000 [24-25] TRBP/RAP250/ASC-2 23054 LLVNLLQS(886-893)
LLSQLLDN(1490-1497)辅激活因子 招募组蛋白乙酰化酶,并参与DNA复制和损伤修复 突变可导致乳腺癌 2000 [26-27] DRIP150/MED14 9282 ALNILLLP(69-76)
VLTDLLPR(1181-1188)辅激活因子 中介体,与众多MEDs形成调节复合体,参与RNA聚合酶II的转录功能 有待研究 2000 [28] CIA 57727 SLINLLAD(386-393) 辅激活因子/辅抑制因子 具备氨酰基-转运RNA连接酶功能,可以与ATP结合,且与雌激素受体的结合不依赖于转录激活区2 有待研究 2001 [29] PNRC2 55629 QLKTLLKV(171-177) 辅激活因子 参与无意义密码子介导的mRNA降解 有待研究 2001 [30] TIP60 10524 MLKRLLRI(492-499) 辅激活因子 组蛋白乙酰化酶复合体NuA4的催化成分,且可以直接使毛细血管扩张共济失调突变基因乙酰化,在细胞修复中发挥作用 有待研究 2001 [31] PERC/PGC-1 133522 LLQKLLLA(155-162)
ILRELLAQ(342-349)
ILRELLAQ(342-349)辅激活因子 转录调节复合体成分之一,可以与RNA结合,参与能量代谢调节和脂肪细胞分化 基因突变可导致乳腺癌、肥胖、2型糖尿病,在甲状腺嗜酸细胞瘤中过量表达 2002 [32-33] TRAP100/MED24 9862 SLDLLLAA(447-454)
ILPGLLTD(787-794)辅激活因子 中介体,与众多MEDs形成调节复合体,参与RNA聚合酶II的转录功能 在乳腺癌中过量表达 2002 [34-35] MNAR/PELP1 27043 CLLSLLYG(28-35)
VLRDLLRY(72-79)
HLPGLLTS(94-101)
LLTSLLGL(98-105)
ELHSLLAS(181-188)
SLHTLLGA(188-195)
PLRLLLLP(281-289)
LLTHLLSD(376-383)
ELYCLLLA(496-503)
LLALLLAP(501-508)辅激活因子 可以与生长因子信号通路中组分表皮生长因子受体、肝细胞生长因子调节酪氨酸激酶作用物等相互作用,通过视网膜母细胞瘤抑制蛋白1在雌激素介导的细胞周期进展中发挥作用,并且同SRC、磷脂酰肌醇3激酶、信号转导和转录激活子3等相互作用 细胞质内浓度增高时可以导致乳腺癌,过量表达可导致子宫内膜癌、涎腺导管癌等 2004 [36-37] MLL2 8055 RLRELLIR(2685-2691)
HLDDLLNG(3037-3043)
QLQALLMQ(4221-4227)
PLOGLLGC(4252-4258)
LLQKLLRA(4187-4194)
RLRLLLTT(4714-4721)辅激活因子 具有甲基转移酶的功能,可以使组蛋白H3的Lys-3甲基化,被雌激素受体1所招募激活雌激素受体功能 缺失可导致Kabuki综合征,在乳腺癌中过量表达 2006 [38-39] CCDC62/ERAP75 84600 KLQRLLAE(633-640)
ELSTLLPI(649-656)辅激活因子 可以增强雌激素介导的cyclinD1的表达和促进细胞的生长 在前列腺癌细胞中广泛表达 2009 [40] ACTN-4 43707 KLMLLLEV(83-90) 辅激活因子 肌动蛋白结合蛋白,苯丙胺调节转录因子复合物的组成部分 突变可导致1型局灶节段性肾小球硬化 2011 [41] DAX-1 190 ILYSLLTS(145-152) 辅抑制因子 可与核受体亚家族5-A组-成员1蛋白和核受体亚家族0-B组-成员2蛋白形成多异聚体,并招募其他辅抑制子,在肾上腺激素轴的发育中具有重要作用 缺失可导致X染色体偶联的阿狄森氏病和剂量敏感性性反转 2000 [8] SHP-1 5777 ILYALLTS(19-26) 辅抑制因子 可以与DNA直接结合 突变与早发性肥胖有关 2000 [8] RIP140 8204 YLEGLLMH(20-27)
LLASLLQS(132-139)
HLKTLLKK(184-191)
QLALLLSS(265-272)
LLLHLLKS(379-386)
LLLLLLGH(499-506)
VLQLLLGN(712-719)
LLSRLLRQ(818-825)
VLKQLLLS(935-972)辅抑制因子 招募组蛋白去乙酰化酶1、组蛋白去乙酰化酶3等组蛋白去乙酰化酶,并与核受体辅激活子1形成复合物 突变可导致子宫内膜癌和不孕 2001 [42] R-MGMT 4255 VLWKLLKV(95-105) 辅抑制因子 具有甲基转移酶的活性,在DNA损伤后,可以抑制雌激素受体介导的细胞增殖 基因突变或单倍体可导致膀胱癌和脑部肿瘤,在肺癌中过量表达 2001 [43] LCoR 84458 VLSKLLMA(52-59) 辅抑制因子 可以与DNA直接结合,招募羧基末端结合蛋白1、组蛋白去乙酰化酶3、组蛋白去乙酰化酶6等共同组成转录辅抑制复合物 有待研究 2003 [44] REA 11331 ALKLLLGA(22-29) 辅抑制因子 中介体,招募组蛋白去乙酰化酶 在乳腺癌中低表达 2003 [45] ERR10/NAG7 29931 FLIWLLCW(336-343)
FLPHLLNQ(322-329)辅抑制因子 抑制雌激素受体调c-Jun氨基末端激酶琢的活性/激活蛋白,并上1/金属基质蛋白酶1信号通路 在胃肠肿瘤中高表达,可以增强鼻咽癌的侵袭能力 2004 [46] PROX1 5629 VLRKLLKR(69-76) 辅抑制因子 在机体的神经系统和内脏发育中发挥重要作用 低表达可导致肝癌、胰腺癌等 2006 [47] ERK8 9606 TLDALLPP(264-271)
LLRRLLVF(280-287)辅抑制因子 具备ATP结合活性和苏氨酸/丝氨酸激酶的活性,参与蛋白的磷酸化 有待研究 2011 [48] 注:CBP:CREB结合蛋白;SRC:类固醇受体辅激活因子;SRC-1/NCOA-1:类固醇/核受体辅激活因子1;SRC2/GRIP1:类固醇受体激活子2/糖皮质激素受体作用蛋白1;PCAF:P300/CBP相关因子;TRAP220:甲状腺激素受体相关蛋白220;MED:甲基化CpG结合核酸内切酶;DRIP205:维生素D受体作用蛋白205;PIBP:磷酸肌醇结合蛋白;SRC3/AIB1:类固醇受体辅激活因子3/乳腺癌扩增性抗原1;NCOA3:核受体辅激活子3;NRIF3:核受体作用因子3;ITGB3BP:整合素β3结合蛋白;ASC-1:激活信号辅整合子1;LZIP:亮氨酸拉链转录分子;CREB:环磷酸腺苷反应元件结合蛋白;PGC-1:过氧化物酶体增殖物激活受体γ辅激活因子1;TRBP:反式激活RNA结合蛋白;RAP250:核受体激活蛋白250;DRIP150:维生素D受体作用蛋白150;CIA:非依赖AF-2功能的辅激活因子;PNRC2:脯氨酸富集核受体辅激活因子2;TIP60:1型作用蛋白60;TRAP100:甲状腺激素受体相关蛋白100;PERC:过氧化物酶体增殖物激活受体辅激活因子;MNAR:雌激素受体非基因作用调节因子;PELP1:脯氨酸-谷氨酸-亮氨酸富集蛋白1;MLL2:混合谱系白血病基因编码蛋白2;CCDC 62:螺旋化螺旋结构域蛋白62;ERAP75:雌激素受体相关蛋白75;ACTN-4:辅肌动蛋白4;DAX-1:先天性肾上腺发育不良基因编码蛋白;SHP-1:包含SH-2功能域的蛋白酪氨酸磷酸酶1;RIP140:受体相互作用蛋白140;R-MGMT:DNA修复酶-甲基鸟嘌呤DNA甲基转移酶;LCoR:配体依赖的核受体辅抑制因子;REA:雌激素功能抑制因子;ERR10:雌激素相关受体10;NAG7:N-乙酰-β-D-氨基葡萄糖苷酶7;PROX1:Prospero同源盒基因1;ERK8:细胞外信号调节激酶8。 -
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