BTG2相互作用CCR4-NOT蛋白质复合体的新功能研究
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摘要
人类细胞中BTG/Tob蛋白家族的六个成员(BTG1,BTG2~(PC3/Tis21),BTG3/ANA,BTG4/PC3B,Tob1/Tob和Tob2),在细胞周期调控、细胞生长与分化、DNA损伤修复等方面发挥着重要功能[1-5]。在多种肿瘤如肝癌、乳腺癌、肾癌中,BTG/Tob蛋白表达均降低或缺失,基因敲除小鼠肿瘤发生率明显高于对照组小鼠,表明BTG/Tob蛋白表达下调是肿瘤发生发展过程中的重要分子事件,其作为新的抑癌基因的功能正逐步得到证实。最新研究表明,BTG/Tob还参与细胞核内转录及胞浆mRNA脱腺苷酸化的调控,而与CCR4-NOT蛋白复合体的相互作用是BTG/Tob发挥这一功能的前提条件[6-8]。进化高度保守的CCR4-NOT蛋白复合体具有3'-5'核酸外切酶活性,在人类中包含9个亚基:CNOT1,CNOT2,CNOT3,CNOT6/hCcr4a,CNOT6L/hCcr4b,CNOT7/hCaf1,CNOT8/hPop2,CNOT9和CNOT10。其中,CNOT6,CNOT6L,CNOT7,CNOT8是细胞中主要的腺苷酸酶,通过脱腺苷酸化作用降解mRNA及特定转录产物[10-12],从而在真核生物的基因表达调控中发挥重要作用。
研究发现除BTG4外,所有BTG/Tob家族蛋白均可与高度同源的CNOT7和/或CNOT8相互结合[13-17]。晶体结构研究揭示,由5个α螺旋结构、4个β折叠构成的BTG/Tob区域是BTG/Tob蛋白与CNOT7结合的特征性区域[18-20],而BTG2及Tob1 BoxA和BoxB区域的关键亚基也与CNOT7有相互作用[21],此外,最近还报道Tob1的C端区域也可与CNOT1亚基结合[22]。因此,BTG2及Tob1可通过相互结合作用招募CCR4-NOT复合体促进特定mRNA的脱腺苷酸化以发挥调控转录的功能。更重要的是,BTG/Tob与CNOT7结合复合体结构的形成对BTG/Tob蛋白有效发挥其抗增殖特性同样是必不可少的。这些研究高度提示BTG/Tob蛋白与CCR4-NOT蛋白复合体关系密切,二者相互结合,相互调控,共同参与多种细胞生物学行为的调节。
前期研究发现,CCR4-NOT蛋白复合体在DNA损伤修复、组蛋白甲基化、精子发生等方面均发挥着重要作用,表明除参与mRNA降解之外,CCR4-NOT蛋白复合体各亚基还具有更重要的生物学功能。本研究在前期工作基础上,对CCR4-NOT蛋白复合体在神经系统中的新功能进行初步探索和揭示,旨在补充和完善其功能研究,为进一步阐明CCR4-NOT蛋白复合体的生物学意义提供实验依据。
研究目的
1.广泛研究CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式,初步揭示其在神经系统中的新功能;
2.探讨CCR4-NOT蛋白复合体抑制神经母细胞瘤细胞Neuro-2a分化的作用及可能分子机制。
研究内容和方法
1. BTG2及CCR4-NOT蛋白复合体在正常小鼠中的组织表达模式:利用Northern Blot和Western Blot方法广泛研究BTG2和CCR4-NOT蛋白复合体各亚基在正常小鼠中的组织表达情况,为进一步揭示其功能提供实验基础;
2. CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式:利用Western Blot和β-Gal Staining方法研究CCR4-NOT蛋白复合体各亚基在正常小鼠脑组织中的具体表达情况;培养神经干细胞,少突胶质细胞祖细胞等重要的神经细胞,通过维甲酸、去细胞因子等方法有效诱导其定向分化,利用Western Blot、Immunostaining、siRNA干扰等研究CCR4-NOT蛋白复合体各亚基在小鼠神经细胞中的表达模式及可能发挥的功能。
3. CCR4-NOT蛋白复合体在神经母细胞瘤细胞Neuro-2a中的抑制分化作用:利用Neuro-2a作为神经样细胞分化模型,通过构建siRNA腺病毒载体和表达载体,研究在抑制和过表达CCR4-NOT亚基后对Neuro-2a分化的作用及可能分子机制。
研究结果
1. BTG2及CCR4-NOT蛋白复合体在正常小鼠中的组织表达模式: BTG2基因在正常大鼠肾脏中有较高丰度表达,在肺脏、肝脏、大脑、心脏呈低丰度表达,肌肉、胸腺、脾脏中无表达;CCR4-NOT复合体在小鼠各组织中呈广泛表达,尤其在大脑、肺脏、小肠、睾丸、胸腺、卵巢及脾脏中呈高表达。
2. CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式:CCR4-NOT蛋白复合体主要表达于大脑发育早期及端脑组织,在神经系统的三种主要细胞星形胶质细胞、神经元、少突胶质细胞中均有表达,各亚基间表达模式并不完全相同,部分亚基在神经干细胞中的表达高于在原代培养神经元中的表达,并随神经干细胞分化表达降低。CCR4-NOT复合体在少突胶质细胞祖细胞和少突胶质细胞中表达水平基本一致,但抑制其表达后少突胶质细胞增殖明显受到抑制。
3. CCR4-NOT蛋白复合体在神经母细胞瘤细胞Neuro-2a中的抑制分化作用: CNOT6,CNOT8亚基在Neuro-2a细胞分化过程中表达逐渐降低,抑制其表达后伸出神经突的Neuro-2a细胞比例,神经突的数量、长度都较对照组明显增加,而过表达CNOT6,CNOT8能部分逆转CNOT6,CNOT8“敲除”细胞的表型。抑制CNOT6,CNOT8后,β-catenin的表达高于对照组细胞。
结论
1. CCR4-NOT蛋白复合体表达的时空特异性高度提示其可能是调控神经细胞增殖和分化的重要分子之一,进一步揭示了CCR4-NOT复合体的新功能。
2. CNOT2,CNOT3,CNOT6,CNOT8,CNOT9亚基在神经干细胞中的表达高于原代培养神经元,并随神经干细胞的分化表达逐渐降低,提示这些亚基在神经干细胞发育和分化中可能发挥重要作用。
3. CCR4-NOT蛋白复合体不参与少突胶质细胞祖细胞向少突胶质细胞的分化过程,但在维持细胞增殖和存活中发挥重要作用。
4.抑制CNOT6或CNOT8表达可促进Neuro-2a细胞神经突的生长及延长,而过表达能部分逆转“敲除”细胞表型,其分子机制可能是通过抑制β-catenin等促神经突生长的转录因子活性。
The mammalian BTG/Tob family comprises six proteins (BTG1, BTG2~(PC3/Tis21), BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2) in human cells, which regulate cell cycle progression, cell growth and differentiation, DNA damage repair,tumourigenesis and cancer suppression in a variety of cell types. Down regulation or impaired expression of BTG/Tob is observed in several tumors, including prostate cancer, clear renal cell carcinomas and breast cancer, mice lacking BTG/Tob are prone to spontaneous carcinogenesis with high frequencies of tumors found in liver, lung and lymph nodes, indicating the deregulation of BTG/Tob early at the tumorigenic process may also be an important step in the development of mammary tumors and BTG/Tob as new tumor suppressor is demonstrated by more and more evidence.
Several members of the BTG/Tob family is shown to be implicated in transcription in the nucleus and cytoplasmic mRNA deadenylation and turnover in recent studies, moreover, BTG/Tob factors impact deadenylases through the interaction with DNA-binding transcription factors as well as the paralogues CNOT7 (human Caf1/Caf1a) and CNOT8 (human Pop2/Calif/Caf1b), two deadenylase subunits of the CCR4-NOT complex.
The CCR4–NOT complex conserved from yeast to human is composed of nine subunits, CNOT1, CNOT2, CNOT3, CNOT6/hCcr4a, CNOT6L/hCcr4b, CNOT7/hCaf1, CNOT8/hPop2, CNOT9 and CNOT10, among which CNOT6, 6L, 7, 8 possess exonuclease domain, and are implicated in several aspects of mRNA metabolism, and that both factors have a predominant role in mRNA poly(A) tail shortening in vivo.
Except for BTG4, all BTG/Tob proteins can interact with the highly similar paralogues CNOT7 and/or CNOT8,whose amino acid sequences are 76% identical (89% similar).Studies on crystal structures of the conserved BTG/Tob domain of BTG2 and Tob1 revealed that it is composed of fiveα-helices and fourβ-strands, and this characteristic structure contacts with CNOT7 surface.Moreover, key residues from both box A and box B motifs of Tob1 are involved in the Tob1–CNOT7 interaction, an interaction between Tob1 and the CNOT1 subunit of the large CCR4–NOT assembly was also described recently. These observations suggested that BTG/Tob proteins might direct CNOT7 to its mRNA substrates in controlling mRNA deadenylation. More importantly, the association between Tob and CNOT7 appears to be crucial for the exertion of a strong anti-proliferative activity.
We previously showed that depletion of CNOT6L or CNOT7 subunit of the complex impaired cell growth or spermatogenesis in mice, respectively, suggesting that the CCR4-NOT complex has non-housekeeping functions despite its fundamental cellular function in mRNA metabolism. However, the functions and underlying mechanism of action of most subunits remain largely unknown. To analyze their biological significance, we performed extensive analysis of their expression in mouse central nervous system to establish the foundation for further study of CCR4-NOT complex.
Objective
1 Study extensively on the expression of CCR4-NOT complex in mouse brain tissues and different cell types, and to reveal its new functions in central nervous system.
2 Study the functions and underlying mechanisms of CCR4-NOT complex on cell differentiation by applying the Neuro-2a mouse neuroblastoma cell line as model system.
Materials and Methods
1 Expression of BTG2 and CCR4-NOT complex in various mouse organs: Northern Blot and Western Blot were used for analysis of expression pattern.
2 Expression of CCR4-NOT complex in different regions and cells of brain: Western Blot andβ-Gal Staining were used for analysis of expression pattern. Primary culture of neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs) were induced by retinoic acid (RA) and removal of cytokines. Western Blot、Immunostaining、siRNA were applied for study on the expression and functions of CCR4-NOT complex.
3 The functions of CCR4-NOT complex in Neuro-2a cells: The retrovirus vectors pSIREN-CNOT6 , pSIREN-CNOT8 for knockdown and pMX-EGFP-CNOT6 ,pMX-EGFP-CNOT8 for over expression were constructed. The effect of CCR4-NOT complex on Neuro-2a differentiation was studied after CNOT6 or CNOT8 knockdown and over expression.
Results
1 Expression of BTG2 and CCR4-NOT complex in various mouse organs: BTG2 was expressed abundantly in kidney, lowly in the lung, brain, liver and heart, not expressed in muscle, thymus and spleen.CCR4-NOT complex subunits were expressed in most of mouse tissues, being especially high in the brain, lung, small intestine, testis, thymus, ovary, and spleen.
2 Expression of CCR4-NOT complex in different regions and cells of brain: We further found that all CCR4-NOT subunits were highly expressed in the olfactory bulb, cerebral cortex, hippocampus and cerebellum of mouse brains, moreover, they were highly expressed at early developmental stages. The brain consists of three major types of cells: astrocytes, neurons, and oligodendrocytes. All CCR4-NOT subunits were expressed in these three cell types, being particularly high in oligodendrocytes. The expression of several subunits of the CCR4-NOT complex were down-regulated in primary cultured neurons compared with in neural stem cells. The expression of CCR4-NOT complex were the same in OPCs and oligodendrycytes(OLs), but cell proliferation of OLs were inhibited after CCR4-NOT complex knock down.
3 The functions of CCR4-NOT complex in Neuro-2a cells: CONT6 or CNOT8 deletion promotes neurite outgrowth of Neuro-2a, on contrast, CONT6 or CNOT8 over expression inhibits neurite outgrowth, furthermore, over expression rescues the phenotype of CONT6 or CNOT8 knock down Neuro-2a cells,β-catenin was also unregulated in CONT6 or CNOT8 knock down cells.
Conclusions
1 CCR4–NOT complex may be a pivotal factor involved in the regulation of cell proliferation and differentiation, demonstrated by the expression pattern in the mouse brain.
2 CNOT2, CNOT3, CNOT6, CNOT8, CNOT9 were down-regulated in primary cultured neurons compared with in NSCs, indicating CCR4–NOT complex may be required for maintaining the undifferentiated state of neural stem cells and involved in early neuronal differentiation or proliferation of NSCs.
3 CCR4–NOT complex was not required in the differentiation of OPCs to OLs, but it play important role in regulating the proliferation of OLs.
4 The inhibitory effect of CCR4–NOT complex on neurite outgrowth of Neuro-2a indicates that it may function during neuronal maturation throughβ-catenin inactivation.
研究发现除BTG4外,所有BTG/Tob家族蛋白均可与高度同源的CNOT7和/或CNOT8相互结合[13-17]。晶体结构研究揭示,由5个α螺旋结构、4个β折叠构成的BTG/Tob区域是BTG/Tob蛋白与CNOT7结合的特征性区域[18-20],而BTG2及Tob1 BoxA和BoxB区域的关键亚基也与CNOT7有相互作用[21],此外,最近还报道Tob1的C端区域也可与CNOT1亚基结合[22]。因此,BTG2及Tob1可通过相互结合作用招募CCR4-NOT复合体促进特定mRNA的脱腺苷酸化以发挥调控转录的功能。更重要的是,BTG/Tob与CNOT7结合复合体结构的形成对BTG/Tob蛋白有效发挥其抗增殖特性同样是必不可少的。这些研究高度提示BTG/Tob蛋白与CCR4-NOT蛋白复合体关系密切,二者相互结合,相互调控,共同参与多种细胞生物学行为的调节。
前期研究发现,CCR4-NOT蛋白复合体在DNA损伤修复、组蛋白甲基化、精子发生等方面均发挥着重要作用,表明除参与mRNA降解之外,CCR4-NOT蛋白复合体各亚基还具有更重要的生物学功能。本研究在前期工作基础上,对CCR4-NOT蛋白复合体在神经系统中的新功能进行初步探索和揭示,旨在补充和完善其功能研究,为进一步阐明CCR4-NOT蛋白复合体的生物学意义提供实验依据。
研究目的
1.广泛研究CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式,初步揭示其在神经系统中的新功能;
2.探讨CCR4-NOT蛋白复合体抑制神经母细胞瘤细胞Neuro-2a分化的作用及可能分子机制。
研究内容和方法
1. BTG2及CCR4-NOT蛋白复合体在正常小鼠中的组织表达模式:利用Northern Blot和Western Blot方法广泛研究BTG2和CCR4-NOT蛋白复合体各亚基在正常小鼠中的组织表达情况,为进一步揭示其功能提供实验基础;
2. CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式:利用Western Blot和β-Gal Staining方法研究CCR4-NOT蛋白复合体各亚基在正常小鼠脑组织中的具体表达情况;培养神经干细胞,少突胶质细胞祖细胞等重要的神经细胞,通过维甲酸、去细胞因子等方法有效诱导其定向分化,利用Western Blot、Immunostaining、siRNA干扰等研究CCR4-NOT蛋白复合体各亚基在小鼠神经细胞中的表达模式及可能发挥的功能。
3. CCR4-NOT蛋白复合体在神经母细胞瘤细胞Neuro-2a中的抑制分化作用:利用Neuro-2a作为神经样细胞分化模型,通过构建siRNA腺病毒载体和表达载体,研究在抑制和过表达CCR4-NOT亚基后对Neuro-2a分化的作用及可能分子机制。
研究结果
1. BTG2及CCR4-NOT蛋白复合体在正常小鼠中的组织表达模式: BTG2基因在正常大鼠肾脏中有较高丰度表达,在肺脏、肝脏、大脑、心脏呈低丰度表达,肌肉、胸腺、脾脏中无表达;CCR4-NOT复合体在小鼠各组织中呈广泛表达,尤其在大脑、肺脏、小肠、睾丸、胸腺、卵巢及脾脏中呈高表达。
2. CCR4-NOT蛋白复合体在小鼠脑组织及神经细胞中的表达模式:CCR4-NOT蛋白复合体主要表达于大脑发育早期及端脑组织,在神经系统的三种主要细胞星形胶质细胞、神经元、少突胶质细胞中均有表达,各亚基间表达模式并不完全相同,部分亚基在神经干细胞中的表达高于在原代培养神经元中的表达,并随神经干细胞分化表达降低。CCR4-NOT复合体在少突胶质细胞祖细胞和少突胶质细胞中表达水平基本一致,但抑制其表达后少突胶质细胞增殖明显受到抑制。
3. CCR4-NOT蛋白复合体在神经母细胞瘤细胞Neuro-2a中的抑制分化作用: CNOT6,CNOT8亚基在Neuro-2a细胞分化过程中表达逐渐降低,抑制其表达后伸出神经突的Neuro-2a细胞比例,神经突的数量、长度都较对照组明显增加,而过表达CNOT6,CNOT8能部分逆转CNOT6,CNOT8“敲除”细胞的表型。抑制CNOT6,CNOT8后,β-catenin的表达高于对照组细胞。
结论
1. CCR4-NOT蛋白复合体表达的时空特异性高度提示其可能是调控神经细胞增殖和分化的重要分子之一,进一步揭示了CCR4-NOT复合体的新功能。
2. CNOT2,CNOT3,CNOT6,CNOT8,CNOT9亚基在神经干细胞中的表达高于原代培养神经元,并随神经干细胞的分化表达逐渐降低,提示这些亚基在神经干细胞发育和分化中可能发挥重要作用。
3. CCR4-NOT蛋白复合体不参与少突胶质细胞祖细胞向少突胶质细胞的分化过程,但在维持细胞增殖和存活中发挥重要作用。
4.抑制CNOT6或CNOT8表达可促进Neuro-2a细胞神经突的生长及延长,而过表达能部分逆转“敲除”细胞表型,其分子机制可能是通过抑制β-catenin等促神经突生长的转录因子活性。
The mammalian BTG/Tob family comprises six proteins (BTG1, BTG2~(PC3/Tis21), BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2) in human cells, which regulate cell cycle progression, cell growth and differentiation, DNA damage repair,tumourigenesis and cancer suppression in a variety of cell types. Down regulation or impaired expression of BTG/Tob is observed in several tumors, including prostate cancer, clear renal cell carcinomas and breast cancer, mice lacking BTG/Tob are prone to spontaneous carcinogenesis with high frequencies of tumors found in liver, lung and lymph nodes, indicating the deregulation of BTG/Tob early at the tumorigenic process may also be an important step in the development of mammary tumors and BTG/Tob as new tumor suppressor is demonstrated by more and more evidence.
Several members of the BTG/Tob family is shown to be implicated in transcription in the nucleus and cytoplasmic mRNA deadenylation and turnover in recent studies, moreover, BTG/Tob factors impact deadenylases through the interaction with DNA-binding transcription factors as well as the paralogues CNOT7 (human Caf1/Caf1a) and CNOT8 (human Pop2/Calif/Caf1b), two deadenylase subunits of the CCR4-NOT complex.
The CCR4–NOT complex conserved from yeast to human is composed of nine subunits, CNOT1, CNOT2, CNOT3, CNOT6/hCcr4a, CNOT6L/hCcr4b, CNOT7/hCaf1, CNOT8/hPop2, CNOT9 and CNOT10, among which CNOT6, 6L, 7, 8 possess exonuclease domain, and are implicated in several aspects of mRNA metabolism, and that both factors have a predominant role in mRNA poly(A) tail shortening in vivo.
Except for BTG4, all BTG/Tob proteins can interact with the highly similar paralogues CNOT7 and/or CNOT8,whose amino acid sequences are 76% identical (89% similar).Studies on crystal structures of the conserved BTG/Tob domain of BTG2 and Tob1 revealed that it is composed of fiveα-helices and fourβ-strands, and this characteristic structure contacts with CNOT7 surface.Moreover, key residues from both box A and box B motifs of Tob1 are involved in the Tob1–CNOT7 interaction, an interaction between Tob1 and the CNOT1 subunit of the large CCR4–NOT assembly was also described recently. These observations suggested that BTG/Tob proteins might direct CNOT7 to its mRNA substrates in controlling mRNA deadenylation. More importantly, the association between Tob and CNOT7 appears to be crucial for the exertion of a strong anti-proliferative activity.
We previously showed that depletion of CNOT6L or CNOT7 subunit of the complex impaired cell growth or spermatogenesis in mice, respectively, suggesting that the CCR4-NOT complex has non-housekeeping functions despite its fundamental cellular function in mRNA metabolism. However, the functions and underlying mechanism of action of most subunits remain largely unknown. To analyze their biological significance, we performed extensive analysis of their expression in mouse central nervous system to establish the foundation for further study of CCR4-NOT complex.
Objective
1 Study extensively on the expression of CCR4-NOT complex in mouse brain tissues and different cell types, and to reveal its new functions in central nervous system.
2 Study the functions and underlying mechanisms of CCR4-NOT complex on cell differentiation by applying the Neuro-2a mouse neuroblastoma cell line as model system.
Materials and Methods
1 Expression of BTG2 and CCR4-NOT complex in various mouse organs: Northern Blot and Western Blot were used for analysis of expression pattern.
2 Expression of CCR4-NOT complex in different regions and cells of brain: Western Blot andβ-Gal Staining were used for analysis of expression pattern. Primary culture of neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs) were induced by retinoic acid (RA) and removal of cytokines. Western Blot、Immunostaining、siRNA were applied for study on the expression and functions of CCR4-NOT complex.
3 The functions of CCR4-NOT complex in Neuro-2a cells: The retrovirus vectors pSIREN-CNOT6 , pSIREN-CNOT8 for knockdown and pMX-EGFP-CNOT6 ,pMX-EGFP-CNOT8 for over expression were constructed. The effect of CCR4-NOT complex on Neuro-2a differentiation was studied after CNOT6 or CNOT8 knockdown and over expression.
Results
1 Expression of BTG2 and CCR4-NOT complex in various mouse organs: BTG2 was expressed abundantly in kidney, lowly in the lung, brain, liver and heart, not expressed in muscle, thymus and spleen.CCR4-NOT complex subunits were expressed in most of mouse tissues, being especially high in the brain, lung, small intestine, testis, thymus, ovary, and spleen.
2 Expression of CCR4-NOT complex in different regions and cells of brain: We further found that all CCR4-NOT subunits were highly expressed in the olfactory bulb, cerebral cortex, hippocampus and cerebellum of mouse brains, moreover, they were highly expressed at early developmental stages. The brain consists of three major types of cells: astrocytes, neurons, and oligodendrocytes. All CCR4-NOT subunits were expressed in these three cell types, being particularly high in oligodendrocytes. The expression of several subunits of the CCR4-NOT complex were down-regulated in primary cultured neurons compared with in neural stem cells. The expression of CCR4-NOT complex were the same in OPCs and oligodendrycytes(OLs), but cell proliferation of OLs were inhibited after CCR4-NOT complex knock down.
3 The functions of CCR4-NOT complex in Neuro-2a cells: CONT6 or CNOT8 deletion promotes neurite outgrowth of Neuro-2a, on contrast, CONT6 or CNOT8 over expression inhibits neurite outgrowth, furthermore, over expression rescues the phenotype of CONT6 or CNOT8 knock down Neuro-2a cells,β-catenin was also unregulated in CONT6 or CNOT8 knock down cells.
Conclusions
1 CCR4–NOT complex may be a pivotal factor involved in the regulation of cell proliferation and differentiation, demonstrated by the expression pattern in the mouse brain.
2 CNOT2, CNOT3, CNOT6, CNOT8, CNOT9 were down-regulated in primary cultured neurons compared with in NSCs, indicating CCR4–NOT complex may be required for maintaining the undifferentiated state of neural stem cells and involved in early neuronal differentiation or proliferation of NSCs.
3 CCR4–NOT complex was not required in the differentiation of OPCs to OLs, but it play important role in regulating the proliferation of OLs.
4 The inhibitory effect of CCR4–NOT complex on neurite outgrowth of Neuro-2a indicates that it may function during neuronal maturation throughβ-catenin inactivation.
引文
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1. Rouault, J.P. et al. BTG1, a member of a new family of antiproliferative genes. EMBO J,1992,11, 1663–1670
2. Matsuda, S. et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene, 1996, 12, 705–713
3. Yoshida, Y. et al. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene ,1998,16, 2687–2693
4. Ikematsu, N. et al. Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of cyclin- dependent kinases. Oncogene, 1999 , 18, 7432–7441
5. Buanne, P. et al. Cloning of PC3B, a novel member of the PC3/ BTG/TOB family of growth inhibitory genes, highly expressed in the olfactory epithelium. Genomics,2000, 68, 253–263
6. Bradbury A, Possenti R,et al. Molecular cloning of PC3, a putatively secreted protein whosemRNAis induced by nerve growth factor and depolarization. Proc Natl Acad Sci USA,1991, 88,3353–3357
7. Fletcher BS, Lim RW,et al. Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. J Biol Chem,1991, 266,14511–14518
8. Rouault JP, Rimokh R, Tessa C, et al. BTG1, a member of a new family of antiproliferative genes. EMBO J,1992, 11,1663–1670
9. Matsuda S, Kawamura-Tsuzuku J, et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene ,1996,12,705–713
10. Guehenneux F, Duret L, et al. Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle. Leukemia ,1997,11,370–375
11. Yoshida Y, Matsuda S, Ikematsu N, et al. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene ,1998,16,2687–2693
12. Ikematsu N, Yoshida Y, Kawamura-Tsuzuku J,et al. Tob2, a novel anti-proliferativeTob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinases. Oncogene,1999, 18,7432–7441
13. Buanne P, Corrente G, et al. Cloning of PC3B, a novel member of the PC3/BTG/TOB family of growth inhibitory genes, highly expressed in the olfactory epithelium. Genomics ,2000,68,253–263
14. Matsuda S, Rouault J, Magaud J, et al. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett ,2002,497,67–72
15. Tirone F et al. The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: Regulator in control of cell growth, differentiation, and DNA repair? J Cell Physiol ,2001,187,155–165
16. Prevot D, Voeltzel T, Birot AM, et al. The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem ,2000,275,147–153
17. Ou YH, Chung PH, Hsu FF, et al. The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1. EMBO J ,2007,26,3968–3980
18. Rouault JP, Prevot D, Berthet C,et al. Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem ,1998,273,22563–22569
19. Prevot D, Morel AP, Voeltzel T, et al. Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: Involvement in estrogen receptor alpha signaling pathway. J Biol Chem,2001, 276,9640–9648
20. Yoshida Y, Hosoda E, Nakamura T, Yamamoto T. Association of ANA, a member of the antiproliferative Tob family proteins, with a Caf1 component of the CCR4 transcriptional regulatory complex. Jpn J Cancer Res ,2001,92,592–596
21. Ezzeddine N, Chang TC, et al. Human TOB, an antiproliferative transcription factor, is a poly(A)-binding protein-dependent positive regulator of cytoplasmic mRNA deadenylation. Mol Cell Biol ,2007,27,7791–7801
22. Farioli-Vecchioli S, Tanori M, Micheli L,et al. Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3. FASEBJ ,2007,21,2215–2225
23. Mauxion F, Faux C, Seraphin B. The BTG2 protein is a general activator of mRNA deadenylation. EMBO J ,2008,27,1039–1048
24. Yang X, Morita M, Wang H, et al. Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic Acids Res ,2008,36, 6872–6881
25. Horiuchi M, Takeuchi K, Noda N, et al. Structural basis for the antiproliferative activity of the Tob-hCaf1 complex. J Biol Chem ,2009,284,13244–13255
26. Aslam A, Mittal S,et al. The Ccr4-Not deadenylase subunitsCNOT7 and CNOT8 have overlapping roles and modulate cell proliferation. Mol Biol Cell,2009,20,3840–3850
27. Tzachanis D, FreemanGJ, HiranoN, et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol ,2001,2,1174–1182
28. Passeri D, Marcucci A, Rizzo G, et al. Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Mol Cell Biol ,2006,26,5023–5032
29. Morita M, Suzuki T, Nakamura T, et al. Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1mRNAlevel and impairs cell growth. Mol Cell Biol ,2007,27,4980–4990
30. Funakoshi Y, Doi Y,et al. Mechanism of mRNA deadenylation: Evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases. Genes Dev ,2007,21,3135–3148
31. Cougot N, Babajko S, Seraphin B. Cytoplasmic foci are sites of mRNA decay in human cells. J Cell Biol,2004, 165,31–40
32. Kawamura-Tsuzuku J, Suzuki T, Yoshida Y, et al. Nuclear localization of Tob is important for regulation of its antiproliferative activity. Oncogene,2004, 23,6630–6638
33. Maekawa M, Yamamoto T, Nishida E. Regulation of subcellular localization of the antiproliferative protein Tob by its nuclear export signal and bipartite nuclear localization signal sequences. Exp Cell Res ,2004,295,59–65
34. Donato LJ, Suh JH, Noy N. Suppression ofmammary carcinoma cell growth by retinoic acid: The cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res ,2007,67,609–615
35. Bianchin C, Mauxion F, et al. Conservation of the deadenylase activity of proteins of the Caf1 family in human. RNA ,2005,11,487–494
36. Rodier A, Marchal-Victorion S, Rochard P, et al. BTG1: A triiodothyronine target involved in the myogenic influence of the hormone. Exp Cell Res ,1999,249,337–348
37. Rouault JP, Falette N, Guehenneux F, et al. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat Genet ,1996,14,482–486
38. Boiko AD, Porteous S, et al. A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev ,2006,20,236–252
39. Yoshida Y, Tanaka S, Yamamoto T,et al. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell ,2000,103,1085–1097
40. Yoshida Y, von Bubnoff A, Ikematsu N,et al. Tob proteins enhance inhibitory Smadreceptor interactions to repress BMP signaling. Mech Dev ,2003b,120,629–637
41. Park S, Lee YJ, LeeHJ, et al. B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating bone morphogenetic protein/smad signaling. Mol Cell Biol ,2004,24,10256–10262
42. Yoshida Y, Nakamura T, Komoda M,et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev ,2003a,17,1201–1206
43. Yoneda M, Suzuki T, Nakamura T, et al. Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma. Cancer Sci ,2009,100, 225–232
44. Yanagie H, Tanabe T, Sumimoto H, et al. Tumor growth suppression by adenovirus- mediated introduction of a cell growth suppressing gene tob in a pancreatic cancer model. Biomed Pharmacother,2009, 63,275–286
45. Iwanaga K, SueokaN, Sato A,et al. Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer. Cancer Lett ,2003,202,71–79
46. Ito Y, Suzuki T, Yoshida H,et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett, 2005,220,237–242
47. Ficazzola MA, Fraiman M, et al. Antiproliferative B cell translocation gene 2 protein isdown-regulated posttranscriptionally as an early event in prostate carcinogenesis. Carcinogenesis,2001, 22,1271–1279
48. Kawakubo H, Brachtel E,Hayashida T,et al. Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein. Cancer Res ,2006,66,7075–7082
49. Struckmann K, Schraml P, Simon R,et al. Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer Res ,2004,64, 1632–1638
50. Majid S, Dar AA, Ahmad A,et al. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis , 2009,30,662–670
51. Collart MA, Timmers HT. The eukaryotic Ccr4-not complex: A regulatory platform integratingmRNAmetabolism with cellular signaling pathways? Prog Nucleic Acid Res Mol Biol,2004,77,289–322
2. Aslam A, Mittal S, Koch F, et al. The Ccr4-Not deadenylase subunits CNOT7 and CNOT8 have overlapping roles and modulate cell proliferation. Mol Biol Cell, 2009 ,20:3840–3850
3. Bedford MT, Clarke SG. Protein arginine methylation in mammals: Who, what, and why. Mol Cell ,2009 ,33:1–13
4. Berthet C, Guehenneux F, Revol V, et al. Interaction of PRMT1 with BTG/TOB proteins in cell signalling: Molecular analysis and functional aspects. Genes Cells, 2002 ,7:29–39
5. Bianchin C, Mauxion F, Sentis S, etal. Conservation of the deadenylase activity of proteins of the Caf1 family in human. RNA ,2005 ,11:487–494
6. Boiko AD, Porteous S, Razorenova OV, etal. A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev,2006 ,20:236–252
7. Bradbury A, Possenti R, Shooter EM,etal. Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization. Proc Natl Acad Sci USA ,1991, 88:3353–3357
8. Buanne P, Corrente G, Micheli L,etal. Cloning of PC3B, a novel member of the PC3/ BTG/TOB family of growth inhibitory genes, highly expressed in the olfactory epithelium. Genomics,2000, 68:253–263
9. Busson M, Carazo A, Seyer P,etal. Coactivation of nuclear receptors and myogenic factorsinduces the major BTG1 influence on muscle differentiation. Oncogene , 2005,24:1698–1710
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8. Rouault JP, Rimokh R, Tessa C, et al. BTG1, a member of a new family of antiproliferative genes. EMBO J,1992, 11,1663–1670
9. Matsuda S, Kawamura-Tsuzuku J, et al. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene ,1996,12,705–713
10. Guehenneux F, Duret L, et al. Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle. Leukemia ,1997,11,370–375
11. Yoshida Y, Matsuda S, Ikematsu N, et al. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene ,1998,16,2687–2693
12. Ikematsu N, Yoshida Y, Kawamura-Tsuzuku J,et al. Tob2, a novel anti-proliferativeTob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinases. Oncogene,1999, 18,7432–7441
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16. Prevot D, Voeltzel T, Birot AM, et al. The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem ,2000,275,147–153
17. Ou YH, Chung PH, Hsu FF, et al. The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1. EMBO J ,2007,26,3968–3980
18. Rouault JP, Prevot D, Berthet C,et al. Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem ,1998,273,22563–22569
19. Prevot D, Morel AP, Voeltzel T, et al. Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: Involvement in estrogen receptor alpha signaling pathway. J Biol Chem,2001, 276,9640–9648
20. Yoshida Y, Hosoda E, Nakamura T, Yamamoto T. Association of ANA, a member of the antiproliferative Tob family proteins, with a Caf1 component of the CCR4 transcriptional regulatory complex. Jpn J Cancer Res ,2001,92,592–596
21. Ezzeddine N, Chang TC, et al. Human TOB, an antiproliferative transcription factor, is a poly(A)-binding protein-dependent positive regulator of cytoplasmic mRNA deadenylation. Mol Cell Biol ,2007,27,7791–7801
22. Farioli-Vecchioli S, Tanori M, Micheli L,et al. Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3. FASEBJ ,2007,21,2215–2225
23. Mauxion F, Faux C, Seraphin B. The BTG2 protein is a general activator of mRNA deadenylation. EMBO J ,2008,27,1039–1048
24. Yang X, Morita M, Wang H, et al. Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic Acids Res ,2008,36, 6872–6881
25. Horiuchi M, Takeuchi K, Noda N, et al. Structural basis for the antiproliferative activity of the Tob-hCaf1 complex. J Biol Chem ,2009,284,13244–13255
26. Aslam A, Mittal S,et al. The Ccr4-Not deadenylase subunitsCNOT7 and CNOT8 have overlapping roles and modulate cell proliferation. Mol Biol Cell,2009,20,3840–3850
27. Tzachanis D, FreemanGJ, HiranoN, et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol ,2001,2,1174–1182
28. Passeri D, Marcucci A, Rizzo G, et al. Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Mol Cell Biol ,2006,26,5023–5032
29. Morita M, Suzuki T, Nakamura T, et al. Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1mRNAlevel and impairs cell growth. Mol Cell Biol ,2007,27,4980–4990
30. Funakoshi Y, Doi Y,et al. Mechanism of mRNA deadenylation: Evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases. Genes Dev ,2007,21,3135–3148
31. Cougot N, Babajko S, Seraphin B. Cytoplasmic foci are sites of mRNA decay in human cells. J Cell Biol,2004, 165,31–40
32. Kawamura-Tsuzuku J, Suzuki T, Yoshida Y, et al. Nuclear localization of Tob is important for regulation of its antiproliferative activity. Oncogene,2004, 23,6630–6638
33. Maekawa M, Yamamoto T, Nishida E. Regulation of subcellular localization of the antiproliferative protein Tob by its nuclear export signal and bipartite nuclear localization signal sequences. Exp Cell Res ,2004,295,59–65
34. Donato LJ, Suh JH, Noy N. Suppression ofmammary carcinoma cell growth by retinoic acid: The cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res ,2007,67,609–615
35. Bianchin C, Mauxion F, et al. Conservation of the deadenylase activity of proteins of the Caf1 family in human. RNA ,2005,11,487–494
36. Rodier A, Marchal-Victorion S, Rochard P, et al. BTG1: A triiodothyronine target involved in the myogenic influence of the hormone. Exp Cell Res ,1999,249,337–348
37. Rouault JP, Falette N, Guehenneux F, et al. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat Genet ,1996,14,482–486
38. Boiko AD, Porteous S, et al. A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev ,2006,20,236–252
39. Yoshida Y, Tanaka S, Yamamoto T,et al. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell ,2000,103,1085–1097
40. Yoshida Y, von Bubnoff A, Ikematsu N,et al. Tob proteins enhance inhibitory Smadreceptor interactions to repress BMP signaling. Mech Dev ,2003b,120,629–637
41. Park S, Lee YJ, LeeHJ, et al. B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating bone morphogenetic protein/smad signaling. Mol Cell Biol ,2004,24,10256–10262
42. Yoshida Y, Nakamura T, Komoda M,et al. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev ,2003a,17,1201–1206
43. Yoneda M, Suzuki T, Nakamura T, et al. Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma. Cancer Sci ,2009,100, 225–232
44. Yanagie H, Tanabe T, Sumimoto H, et al. Tumor growth suppression by adenovirus- mediated introduction of a cell growth suppressing gene tob in a pancreatic cancer model. Biomed Pharmacother,2009, 63,275–286
45. Iwanaga K, SueokaN, Sato A,et al. Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer. Cancer Lett ,2003,202,71–79
46. Ito Y, Suzuki T, Yoshida H,et al. Phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid. Cancer Lett, 2005,220,237–242
47. Ficazzola MA, Fraiman M, et al. Antiproliferative B cell translocation gene 2 protein isdown-regulated posttranscriptionally as an early event in prostate carcinogenesis. Carcinogenesis,2001, 22,1271–1279
48. Kawakubo H, Brachtel E,Hayashida T,et al. Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein. Cancer Res ,2006,66,7075–7082
49. Struckmann K, Schraml P, Simon R,et al. Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer Res ,2004,64, 1632–1638
50. Majid S, Dar AA, Ahmad A,et al. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis , 2009,30,662–670
51. Collart MA, Timmers HT. The eukaryotic Ccr4-not complex: A regulatory platform integratingmRNAmetabolism with cellular signaling pathways? Prog Nucleic Acid Res Mol Biol,2004,77,289–322