肿瘤转移相关基因MTA1的定位与功能研究
摘要
肿瘤侵袭转移相关基因MTA1最初是在1993年发现高表达于具有高转移潜能的大鼠乳腺癌细胞系中,后来证实MTA1不仅参与了肿瘤的侵袭转移过程,还参与了肿瘤其他多种恶性能力的调控,如细胞增殖、血管生成、耐放化疗等等,最终导致肿瘤的高复发和不良预后。虽然已经经历了20多年的研究历史,但是我们对于MTA1(cancer metastasis-associated gene1)的作用机制依然所知甚少。目前为止,关于MTA1的作用机制唯一比较清楚的就是核小体重塑和组蛋白脱乙酰化NuRD (Nucleosome Remodeling and histone Deacetylation)复合体。通过NuRD复合体,MTA1参与了多种肿瘤抑癌基因的转录抑制。然而,后来发现MTA1参与的许多过程都不依赖于NuRD复合体,并且NuRD无法解释MTA1对Pax5、BCAS3、FosB等基因的转录激活作用,因此除了NuRD之外,我们推测还存在其他未知的作用机制。至于MTA1的亚细胞定位,现有文献提示MTA1主要定位于胞核,而对于MTA1更精细的亚细胞定位目前还未见相关报道,而对于MTA1是否存在胞浆定位尚存在争议。
一个蛋白在细胞中的精确定位及相互作用信息对于揭示其功能及机制具有非常重要的作用。因此,为了更深入地揭示MTA1在肿瘤中的功能机制,我们首先利用免疫组化,细胞免疫荧光、GFP标签追踪、Western Blot、IP及原位co-IP等多种技术对MTA1的核浆定位进行了一个全面系统地研究。通过对内源及外源MTA1的精确定位检测,我们发现MTA1在胞核及胞浆中均存在明显分布。同时我们还意外地发现MTA1在某些细胞的核膜上也有明显分布,而MTA1稳转高表达细胞系中获得的MTA1定位追踪图片则直接显示MTA1是一个核浆穿梭蛋白。MTA1在所有我们检测过的样品中均有表达,包括人及小鼠成体正常组织、小鼠胚胎组织、结肠癌组织、正常及肿瘤细胞系,表明MTA1在正常及肿瘤细胞均发挥重要作用。在正常成体组织,MTA1在脑、肝、肾及心肌等组织中表达量相对较高,并且除心肌和骨骼肌之外,MTA1主要定位于胞核。在骨骼肌,MTA1与SMN共定位于肌小节中的Z线上。而在小鼠胚胎组织,MTA1在脑、眼、脊髓等神经组织处具有明显高表达,并且在大部分组织中都主要定位于胞浆。通过对高密度结肠癌芯片染色结果的统计分析,我们发现胞核及胞浆MTA1均参与了肿瘤的进展过程,但在肿瘤细胞的分化调控中,核MTA1发挥着主要作用。
MTA1在细胞核中发挥染色质高级结构调控因子的作用。染色质高级结构在调控基因表达及DNA相关生理过程中发挥着其重要的作用。在该部分研究中,我们首次发现肿瘤转移相关基因MTA1是一个染色质高级结构调控因子,它可以导致间期染色质及M期染色体发生显著的去凝聚作用。我们发现在细胞周期中,MTA1与DNA的相互作用呈现一个动态的、周期性的分离与结合的过程,该周期性过程在有丝分裂前期及末期染色质/染色体结构转换的过程中发挥重要作用。虽然MTA1与染色质重塑因子Mi-2具有相互作用并且共同位于NuRD复合体中,但是MTA1的染色质去凝集作用并不依赖于Mi-2。H1可以通过结合于DNA参与维持和稳定染色质的高级结构。我们的实验结果表明MTA1在胞内可以显著降低H1与DNA之间的相互作用,并且在M期MTA1与DNA的周期性结合与分离有助于调控H1与DNA之间的周期性结合能力,从而参与M期染色质与染色体结构的转换调控。虽然MTA1可以导致染色质高级结构发生广泛的去凝集作用,但是MTA1的高表达只对一小部分基因产生了明显的转录调控作用,包括转录激活和转录抑制双重调控作用。MTA1高表达后导致的差异表达基因在分布模式上具有明显的染色体偏向性,并且上调基因和下调基因具有相似的分布趋势。差异基因的精确定位结果显示,上调基因和下调基因大部分以成簇方式分布于染色体的同一区域中,表明MTA1具有结构依赖性的调控模式。因此,在本部分我们发现MTA1具有染色质高级结构调控因子的新功能,该功能在细胞周期中染色质/染色体之间的的结构转变过程中及间期染色质的转录活性中调控中均发挥重要作用。
MTA1在胞浆中通过结合于纺锤体微管发挥抑制纺锤体检验点(SAC)激活的功能。在间期,MTA1少量定位于胞浆,通过与a-tubulin共定位,我们发现这部分MTA1主要沿着微管分布。在M期,MTA1具有周期依赖性的定位模式,其中大部分时间MTA1都主要定位于胞浆,结合于纺锤体微管并随之运动。在MTA1与细胞周期调控功能的探索过程中,我们发现MTA1对nocodazol引起的纺锤体检验点激活具有很明显的抑制作用。MTAl在HCT116细胞中的高表达会导致染色体排列及分离异常,从而显著增加微核及多核细胞的比例,这些现象都是SAC功能异常的标志性特征。TPR是一个核孔复合体蛋白,其在间期参与mRNA及蛋白的核外转运调控,而在M期则发挥SAC的调控功能。通过IP及免疫荧光共定位技术,我们发现MTA1与TPR在间期核膜及M期纺锤体上均具有相互作用。进一步的实验验证结果表明MTA1通过结合并抑制TPR的SAC正向调控功能从而抑制SAC的激活,并且MTA1可以与MAD1-MAD2复合体竞争结合TPR, MTA1高表达可以显著降低MAD1-MAD2的相互作用,而该相互作用在SAC激活过程中发挥着关键的作用。
另外,MTA1的亚细胞定位及相互作用蛋白质组信息提示MTA1还具有RNA调控功能。有文献报道MTAl在核仁中为阴性表达,然而通过对内源及外源MTA1在核仁中的精确检测,我们确认MTA1在核仁中具有普遍但是相对较低的表达水平。高分辨率的免疫电镜技术结果显示MTA1在核仁中主要定位于致密纤维组分区(DFC)及颗粒区(FC)。 MTA1在核仁中的精确定位及相互作用蛋白信息均表明,MTA1在核仁中参与了rRNA的加工剪切及核糖体亚基的装配过程。另外,我们首次发现并确认MTA1在胞浆中存在于大量RNP颗粒中。MTA1RNP颗粒的相关特性分析结果表明,MTA1参与了RNA的运输、稳定性、翻译及应激状态下的储存调控。通过GO分析,我们发现在228个MTA1候选相互作用蛋白中有74(32.5%)个为RNA结合蛋白,并且MTA1相互作用蛋白质组高度富集于RNA调控相关功能类别之下,如RNA加工、剪切、翻译、稳定性、核糖体发生等等。转录组测序结果表明MTA1敲降后对966个可变剪切事件产生了显著影响。并且有趣的是,外源MTA1的高表达对其自身mRNA的可变剪切也具有显著影响。
综上所述,我们发现MTAl是一个在核仁、胞核、核膜及胞浆中穿梭分布的蛋白；其在细胞周期中具有周期性的动态定位模式；利用MTA1的候选相互作用蛋白我们构建了MTA1在整个基因组中的相互作用网络。通过以上定位及相互作用信息结合大量的功能学验证,我们最终确立了MTA1的三大基础功能：1,染色质结构调控；2,RNA调控；3,细胞骨架相关调控。通过这三大基础功能,MTA1在细胞中发挥重要生理的功能, MTA1过表达将导致这些功能的异常调控从而促进肿瘤的发生及进展。
Cancer metastasis-associated gene1(MTA1) was first cloned in1993, in a highly metastatic breast cancer cell line. Afterwards, in addition to metastasis, MTA1was proved to promote multiple malignant behaviors of cancer cells, such as proliferation, angiogenesis, resistance to radiation and chemotherapy, and so on, resulting in a high recurrence and poor prognosis of cancer. However, despite two decades of research on MTA1, the mechanism underlying its function is still obscure. Up to now, only nucleosome remodeling and histone deacetylation (NuRD) has been identified as a complex through which MTA1plays its role in transcriptional repression of genes, especially cancer suppressor genes. However, other MTA1-involved processes independent of NuRD have been indicated. There are also questions concerning how MTA1is involved in activating transcriptions of some genes, such as Pax5, BCAS3, FosB and so on. So, we proposed that there may be other unknown underlying mechanisms urgent to be discovered. As for subcellular localization, the only confirmed fact is that MTA1has an obvious localization in nucleus, but no more other details were revealed. There are still debates on whether MTAl possesses cytoplasmic distribution.
The exact subcellular localization and co-partners of a protein provide good clues to trace its functions and mechanisms. To further explore the mechanisms through which MTA1promotes cancer development, we initiated a performance to give a comprehensive overview on MTA1distribution by multiple molecular technologies, including immunohistochemistory, cell immuno fluorescence, GFP flag tracking, Western Blot, immunoprecipitation and in situ co-IP. Both endogenous and exogenous MTAl have been examined to confirm its existance in both nucleus and cytoplasm. Moreover, we also found an obvious localization of MTA1on nuclear envelope. A vivid image captured in a stably MTA1-transfected cell line indicated a shuttling model of MTA1between nucleus and cytoplasm through nuclear envelop.MTA1was detected in all samples examined, including mouse and human normal adult tissues, mouse embryonic tissues, colon cancer tissues, normal and cancer cell lines indicating a role of MTA1in both normal and cancer cells. In adult normal tissues, MTA1displayed a relativly higher expression in brain, liver, kidney and cardiac muscle, and was localized mainly in nucleus except cardiac and skeletal muscle fibers. In skeletal muscle, MTA1was co-localized with SMN on Z-line in cytoplasm. At the embryonic stage of development, MTA1was higher in nerve tissues such as brain, eye and spinal cord, and mainly expressed in cytoplasm of most tissues. In the colon cancer tissues evaluated by tissue array staining, both nuclear and cytoplasm MTAl were positively correlated with cancer progression. But only nuclear MTAl was associated with cancer cell differentiation.
MTAl works as a higher-order chromatin structure regulator in nucleus. Chromatin structure plays a critical role in determining gene expression pattern and hence cellular biological processes. In this section, we, for the first time, found that Metastasis-associated gene1(MTA1), which has been reported to be a cancer-promoting gene, was a higher-order chromatin structure organizer to decondense the interphase chromatin and mitotic chromosomes. MTAl interacts dynamically with DNA during cell cycle progression, prominently contributing to the mitotic chromatin/chromosome transitions at both prophase and telophase. We showed that the decondensation of interphase chromatin by MTAl is independent of the chromatin remodeling activity of Mi-2with which MTAl interacts to assemble the nucleosome remodeling and histone deacetylation complex (NuRD). H1was reported to stabilize the compact higher-order chromatin structure through its interaction with DNA. Our data showed that MTAl caused a reduced H1-DNA interaction in vivo. Moreover, the dynamic MTA1-DNA interaction in the cell cycle contributed to the periodical H1-DNA interaction, which in turn modulated chromatin structure transitions. Although MTAl drove a global decondensation of chromatin structure, it changed the expression of only a small proportion of genes. After MTAl overexpression, the up-regulated genes were distributed in clusters with down-regulated genes on chromosomes at parallel frequencies. This fact indicates that MTA1induced a structure-dependent, but not only a function-dependent gene set as presumed. Putting the data together, we discovered a novel roleof MTA1as a potent modulator of chromatin higher-order structure to regulate the mitotic chromatin/chromosome structure transitions and interphase chromatin transcription
MTAl inhibits spindle assembly checkpoint (SAC) activation through binding to spindle microtubules in cytoplasm. At interphase, MTAl was confirmed to bind to microtubules in the cytoplasm though at a relatively low level. During mitosis, most of MTA1moved along with the mitotic spindle apparatus in cytoplasm and showed a cell-cycle-dependent distribution pattern. By nocodazol treatment, we showed that MTA1powerfully inhibited spindle assembly checkpoint activation. When overexpressed in HCT116cells, MTAl caused an obviously larger proportion of micronucleated and multinucleated cells due to defectives in chromosomes alignment and separation, which are the typical characteristics of SAC inactivation. Translocated promoter region (TPR) is a member protein of nuclear pore complex (NPC) which functions in nuclear export of mRNAs and proteins at interphase and SAC regulation during mitosis. By immunoprecipitation and co-localization visualization, we confirmed that MTA1collaborates with TPR both at interphase NPC and mitotic spindle apparatus. By further investigation, we proposed that MTA1inhibits SAC activation by direct binding to TPR and competing with MAD1-MAD2complex for TPR, resulting in a reduced MAD1-MAD2interaction, which is essential in SAC activation.
Analysis on subcellular localization and interactome of MTA1indicates a potential role in RNA regulation. MTA1has been reported to be negative in nucleolus. However, by high magnification observation under fluorescence microscope for both endogenous and exogenous MTA1, we found a low but general expression of MTA1in nucleolus. It was showed that MTA1was localized in both DFC and GC regions of nucleolus by high-resolution immunoelectron microscopy. Both the subcellular localization and co-partner identification supported the role of MTA1in rRNA processing and ribosome subunit assembly. We also for the first time located MTA1at cytoplasmic RNP granules which functions in RNA transport, stability maintenance and temporary storage on stress. GO analysis of MTA1interactome also yielded74RNA binding proteins out of228of the interactome (32.5%), involving RNA-regulating processes, such as RNA processing, splicing, translation, stability maintenance, ribosome biogenesis and so on. Transcriptome sequencing revealed significant influence of MTA1depletion by specific siRNA on966alternative splicing events. Interestingly, MTA1itself is under the alternative splicing regulation by MTA1overexpression.
To sum up, we displayed a shuttling distribution model of MTA1among nucleolus, nucleus, nuclear envelope and cytoplasm, confirmed a dynamic distribution pattern of MTA1during the cell cycle, and constructed an interactom network in the whole cell, all of which were integrated to establish the three fundamental roles of MTA1in chromatin higher order structure, cytoskeleton and RNA regulation. Dysregulation of these physiological roles in normal cells by MTA1overexpression may lead to its pathological roles in cancer promotion.
一个蛋白在细胞中的精确定位及相互作用信息对于揭示其功能及机制具有非常重要的作用。因此,为了更深入地揭示MTA1在肿瘤中的功能机制,我们首先利用免疫组化,细胞免疫荧光、GFP标签追踪、Western Blot、IP及原位co-IP等多种技术对MTA1的核浆定位进行了一个全面系统地研究。通过对内源及外源MTA1的精确定位检测,我们发现MTA1在胞核及胞浆中均存在明显分布。同时我们还意外地发现MTA1在某些细胞的核膜上也有明显分布,而MTA1稳转高表达细胞系中获得的MTA1定位追踪图片则直接显示MTA1是一个核浆穿梭蛋白。MTA1在所有我们检测过的样品中均有表达,包括人及小鼠成体正常组织、小鼠胚胎组织、结肠癌组织、正常及肿瘤细胞系,表明MTA1在正常及肿瘤细胞均发挥重要作用。在正常成体组织,MTA1在脑、肝、肾及心肌等组织中表达量相对较高,并且除心肌和骨骼肌之外,MTA1主要定位于胞核。在骨骼肌,MTA1与SMN共定位于肌小节中的Z线上。而在小鼠胚胎组织,MTA1在脑、眼、脊髓等神经组织处具有明显高表达,并且在大部分组织中都主要定位于胞浆。通过对高密度结肠癌芯片染色结果的统计分析,我们发现胞核及胞浆MTA1均参与了肿瘤的进展过程,但在肿瘤细胞的分化调控中,核MTA1发挥着主要作用。
MTA1在细胞核中发挥染色质高级结构调控因子的作用。染色质高级结构在调控基因表达及DNA相关生理过程中发挥着其重要的作用。在该部分研究中,我们首次发现肿瘤转移相关基因MTA1是一个染色质高级结构调控因子,它可以导致间期染色质及M期染色体发生显著的去凝聚作用。我们发现在细胞周期中,MTA1与DNA的相互作用呈现一个动态的、周期性的分离与结合的过程,该周期性过程在有丝分裂前期及末期染色质/染色体结构转换的过程中发挥重要作用。虽然MTA1与染色质重塑因子Mi-2具有相互作用并且共同位于NuRD复合体中,但是MTA1的染色质去凝集作用并不依赖于Mi-2。H1可以通过结合于DNA参与维持和稳定染色质的高级结构。我们的实验结果表明MTA1在胞内可以显著降低H1与DNA之间的相互作用,并且在M期MTA1与DNA的周期性结合与分离有助于调控H1与DNA之间的周期性结合能力,从而参与M期染色质与染色体结构的转换调控。虽然MTA1可以导致染色质高级结构发生广泛的去凝集作用,但是MTA1的高表达只对一小部分基因产生了明显的转录调控作用,包括转录激活和转录抑制双重调控作用。MTA1高表达后导致的差异表达基因在分布模式上具有明显的染色体偏向性,并且上调基因和下调基因具有相似的分布趋势。差异基因的精确定位结果显示,上调基因和下调基因大部分以成簇方式分布于染色体的同一区域中,表明MTA1具有结构依赖性的调控模式。因此,在本部分我们发现MTA1具有染色质高级结构调控因子的新功能,该功能在细胞周期中染色质/染色体之间的的结构转变过程中及间期染色质的转录活性中调控中均发挥重要作用。
MTA1在胞浆中通过结合于纺锤体微管发挥抑制纺锤体检验点(SAC)激活的功能。在间期,MTA1少量定位于胞浆,通过与a-tubulin共定位,我们发现这部分MTA1主要沿着微管分布。在M期,MTA1具有周期依赖性的定位模式,其中大部分时间MTA1都主要定位于胞浆,结合于纺锤体微管并随之运动。在MTA1与细胞周期调控功能的探索过程中,我们发现MTA1对nocodazol引起的纺锤体检验点激活具有很明显的抑制作用。MTAl在HCT116细胞中的高表达会导致染色体排列及分离异常,从而显著增加微核及多核细胞的比例,这些现象都是SAC功能异常的标志性特征。TPR是一个核孔复合体蛋白,其在间期参与mRNA及蛋白的核外转运调控,而在M期则发挥SAC的调控功能。通过IP及免疫荧光共定位技术,我们发现MTA1与TPR在间期核膜及M期纺锤体上均具有相互作用。进一步的实验验证结果表明MTA1通过结合并抑制TPR的SAC正向调控功能从而抑制SAC的激活,并且MTA1可以与MAD1-MAD2复合体竞争结合TPR, MTA1高表达可以显著降低MAD1-MAD2的相互作用,而该相互作用在SAC激活过程中发挥着关键的作用。
另外,MTA1的亚细胞定位及相互作用蛋白质组信息提示MTA1还具有RNA调控功能。有文献报道MTAl在核仁中为阴性表达,然而通过对内源及外源MTA1在核仁中的精确检测,我们确认MTA1在核仁中具有普遍但是相对较低的表达水平。高分辨率的免疫电镜技术结果显示MTA1在核仁中主要定位于致密纤维组分区(DFC)及颗粒区(FC)。 MTA1在核仁中的精确定位及相互作用蛋白信息均表明,MTA1在核仁中参与了rRNA的加工剪切及核糖体亚基的装配过程。另外,我们首次发现并确认MTA1在胞浆中存在于大量RNP颗粒中。MTA1RNP颗粒的相关特性分析结果表明,MTA1参与了RNA的运输、稳定性、翻译及应激状态下的储存调控。通过GO分析,我们发现在228个MTA1候选相互作用蛋白中有74(32.5%)个为RNA结合蛋白,并且MTA1相互作用蛋白质组高度富集于RNA调控相关功能类别之下,如RNA加工、剪切、翻译、稳定性、核糖体发生等等。转录组测序结果表明MTA1敲降后对966个可变剪切事件产生了显著影响。并且有趣的是,外源MTA1的高表达对其自身mRNA的可变剪切也具有显著影响。
综上所述,我们发现MTAl是一个在核仁、胞核、核膜及胞浆中穿梭分布的蛋白；其在细胞周期中具有周期性的动态定位模式；利用MTA1的候选相互作用蛋白我们构建了MTA1在整个基因组中的相互作用网络。通过以上定位及相互作用信息结合大量的功能学验证,我们最终确立了MTA1的三大基础功能：1,染色质结构调控；2,RNA调控；3,细胞骨架相关调控。通过这三大基础功能,MTA1在细胞中发挥重要生理的功能, MTA1过表达将导致这些功能的异常调控从而促进肿瘤的发生及进展。
Cancer metastasis-associated gene1(MTA1) was first cloned in1993, in a highly metastatic breast cancer cell line. Afterwards, in addition to metastasis, MTA1was proved to promote multiple malignant behaviors of cancer cells, such as proliferation, angiogenesis, resistance to radiation and chemotherapy, and so on, resulting in a high recurrence and poor prognosis of cancer. However, despite two decades of research on MTA1, the mechanism underlying its function is still obscure. Up to now, only nucleosome remodeling and histone deacetylation (NuRD) has been identified as a complex through which MTA1plays its role in transcriptional repression of genes, especially cancer suppressor genes. However, other MTA1-involved processes independent of NuRD have been indicated. There are also questions concerning how MTA1is involved in activating transcriptions of some genes, such as Pax5, BCAS3, FosB and so on. So, we proposed that there may be other unknown underlying mechanisms urgent to be discovered. As for subcellular localization, the only confirmed fact is that MTA1has an obvious localization in nucleus, but no more other details were revealed. There are still debates on whether MTAl possesses cytoplasmic distribution.
The exact subcellular localization and co-partners of a protein provide good clues to trace its functions and mechanisms. To further explore the mechanisms through which MTA1promotes cancer development, we initiated a performance to give a comprehensive overview on MTA1distribution by multiple molecular technologies, including immunohistochemistory, cell immuno fluorescence, GFP flag tracking, Western Blot, immunoprecipitation and in situ co-IP. Both endogenous and exogenous MTAl have been examined to confirm its existance in both nucleus and cytoplasm. Moreover, we also found an obvious localization of MTA1on nuclear envelope. A vivid image captured in a stably MTA1-transfected cell line indicated a shuttling model of MTA1between nucleus and cytoplasm through nuclear envelop.MTA1was detected in all samples examined, including mouse and human normal adult tissues, mouse embryonic tissues, colon cancer tissues, normal and cancer cell lines indicating a role of MTA1in both normal and cancer cells. In adult normal tissues, MTA1displayed a relativly higher expression in brain, liver, kidney and cardiac muscle, and was localized mainly in nucleus except cardiac and skeletal muscle fibers. In skeletal muscle, MTA1was co-localized with SMN on Z-line in cytoplasm. At the embryonic stage of development, MTA1was higher in nerve tissues such as brain, eye and spinal cord, and mainly expressed in cytoplasm of most tissues. In the colon cancer tissues evaluated by tissue array staining, both nuclear and cytoplasm MTAl were positively correlated with cancer progression. But only nuclear MTAl was associated with cancer cell differentiation.
MTAl works as a higher-order chromatin structure regulator in nucleus. Chromatin structure plays a critical role in determining gene expression pattern and hence cellular biological processes. In this section, we, for the first time, found that Metastasis-associated gene1(MTA1), which has been reported to be a cancer-promoting gene, was a higher-order chromatin structure organizer to decondense the interphase chromatin and mitotic chromosomes. MTAl interacts dynamically with DNA during cell cycle progression, prominently contributing to the mitotic chromatin/chromosome transitions at both prophase and telophase. We showed that the decondensation of interphase chromatin by MTAl is independent of the chromatin remodeling activity of Mi-2with which MTAl interacts to assemble the nucleosome remodeling and histone deacetylation complex (NuRD). H1was reported to stabilize the compact higher-order chromatin structure through its interaction with DNA. Our data showed that MTAl caused a reduced H1-DNA interaction in vivo. Moreover, the dynamic MTA1-DNA interaction in the cell cycle contributed to the periodical H1-DNA interaction, which in turn modulated chromatin structure transitions. Although MTAl drove a global decondensation of chromatin structure, it changed the expression of only a small proportion of genes. After MTAl overexpression, the up-regulated genes were distributed in clusters with down-regulated genes on chromosomes at parallel frequencies. This fact indicates that MTA1induced a structure-dependent, but not only a function-dependent gene set as presumed. Putting the data together, we discovered a novel roleof MTA1as a potent modulator of chromatin higher-order structure to regulate the mitotic chromatin/chromosome structure transitions and interphase chromatin transcription
MTAl inhibits spindle assembly checkpoint (SAC) activation through binding to spindle microtubules in cytoplasm. At interphase, MTAl was confirmed to bind to microtubules in the cytoplasm though at a relatively low level. During mitosis, most of MTA1moved along with the mitotic spindle apparatus in cytoplasm and showed a cell-cycle-dependent distribution pattern. By nocodazol treatment, we showed that MTA1powerfully inhibited spindle assembly checkpoint activation. When overexpressed in HCT116cells, MTAl caused an obviously larger proportion of micronucleated and multinucleated cells due to defectives in chromosomes alignment and separation, which are the typical characteristics of SAC inactivation. Translocated promoter region (TPR) is a member protein of nuclear pore complex (NPC) which functions in nuclear export of mRNAs and proteins at interphase and SAC regulation during mitosis. By immunoprecipitation and co-localization visualization, we confirmed that MTA1collaborates with TPR both at interphase NPC and mitotic spindle apparatus. By further investigation, we proposed that MTA1inhibits SAC activation by direct binding to TPR and competing with MAD1-MAD2complex for TPR, resulting in a reduced MAD1-MAD2interaction, which is essential in SAC activation.
Analysis on subcellular localization and interactome of MTA1indicates a potential role in RNA regulation. MTA1has been reported to be negative in nucleolus. However, by high magnification observation under fluorescence microscope for both endogenous and exogenous MTA1, we found a low but general expression of MTA1in nucleolus. It was showed that MTA1was localized in both DFC and GC regions of nucleolus by high-resolution immunoelectron microscopy. Both the subcellular localization and co-partner identification supported the role of MTA1in rRNA processing and ribosome subunit assembly. We also for the first time located MTA1at cytoplasmic RNP granules which functions in RNA transport, stability maintenance and temporary storage on stress. GO analysis of MTA1interactome also yielded74RNA binding proteins out of228of the interactome (32.5%), involving RNA-regulating processes, such as RNA processing, splicing, translation, stability maintenance, ribosome biogenesis and so on. Transcriptome sequencing revealed significant influence of MTA1depletion by specific siRNA on966alternative splicing events. Interestingly, MTA1itself is under the alternative splicing regulation by MTA1overexpression.
To sum up, we displayed a shuttling distribution model of MTA1among nucleolus, nucleus, nuclear envelope and cytoplasm, confirmed a dynamic distribution pattern of MTA1during the cell cycle, and constructed an interactom network in the whole cell, all of which were integrated to establish the three fundamental roles of MTA1in chromatin higher order structure, cytoskeleton and RNA regulation. Dysregulation of these physiological roles in normal cells by MTA1overexpression may lead to its pathological roles in cancer promotion.
引文
[1]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat.1993.25(2):165-74.
[2]Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mtal, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem.1994.269(37):22958-63.
[3]Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers:molecular functions and clinical implications. Clin Exp Metastasis.2009.26(3):215-27.
[4]Li W, Ma L, Zhao J, Liu X, Li Z, Zhang Y Expression profile of MTA1 in adult mouse tissues. Tissue Cell. 2009.41(6):390-9.
[5]Kumar R, Wang RA, Bagheri-Yarmand R. Emerging roles of MTA family members in human cancers. Semin Oncol.2003.30(5 Suppl 16):30-7.
[6]Manavathi B, Kumar R. Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem.2007.282(3):1529-33.
[7]Simpson A, Uitto J, Rodeck U, Mahoney MG. Differential expression and subcellular distribution of the mouse metastasis-associated proteins Mtal and Mta3. Gene.2001.273(1):29-39.
[8]Nawa A, Nishimori K, Lin P, et al. Tumor metastasis-associated human MTA1 gene:its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J CellBiochem.2000.79(2):202-12.
[9]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha Hum Pathol.2004.35(4):424-9.
[10]Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol.2006.37(6):656-61.
[11]Rajendra TK, Gonsalvez GB, Walker MP, Shpargel KB, Salz HK, Matera AG A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol.2007.176(6): 831-41.
[12]Walker MP, Rajendra TK, Saieva L, Fuentes JL, Pellizzoni L, Matera AG. SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain. Hurn Mo1 Genet.2008,17(21):3399-410.
[13]Lunn MR, Wang CH. Spinal muscular atrophy. Lancet.2008.371(9630):2120-33.
[14]Burghes AH, Beattie CE. Spinal muscular atrophy:why do low levels of survival motor neuron protein make motor neurons sick. Nat Rev Neurosci.2009.10(8):597-609.
[15]Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell.1998.2(6):851-61.
[16]Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature.1997.389(6648):251-60.
[17]Tremethick DJ. Higher-order structures of chromatin:the elusive 30 nm fiber. Cell.2007.128(4):6514.
[18]Horn PJ, Peterson CL. Molecular biology. Chromatin higher order folding--wrapping up transcription. Science. 2002.297(5588):1824-7.
[19]Carruthers LM, Bednar J, Woodcock CL, Hansen JC. Linker histones stabilize the intrinsic salt-dependent folding of nucleosomal arrays:mechanistic ramifications for higher-order chromatin folding. Biochemistry. 1998.37(42):14776-87.
[20]Thoma F, Koller T, Klug A. Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin. J Cell Biol.1979.83(2 Pt 1):403-27.
[21]Hizume K, Yoshimura SH. Takeyasu K. Linker histone H1 per se can induce three-dimensional folding of chromatin fiber. Biochemistry.2005.44(39):12978-89.
[22]Hamiche A, Schultz P, Ramakrishnan V. Oudet P, Prunell A. Linker histone-dependent DNA structure in linear mononucleosomes. J Mol Biol.1996.257(1):30-42.
[23]Bednar J, Horowitz RA, Grigoryev SA, et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc Natl Acad Sci U S A. 1998.95(24):14173-8.
[24]Allan J, Hartman PG Crane-Robinson C. Aviles FX. The structure of histone H1 and its location in chromatin. Nature.1980.288(5792):675-9.
[25]Travers A. The location of the linker histone on the nucleosome. Trends Biochem Sci.1999.24(1):4-7.
[26]Woodcock CL, Skoultchi AI, Fan Y. Role of linker histone in chromatin structure and function:H1 stoichiometry and nucleosome repeat length. Chromosome Res.2006.14(1):17-25.
[27]Fan Y, Nikitina T, Morin-Kensicki EM. et al. H1 linker histones are essential for mouse development and affect nucleosome spacing in vivo. Mo1 Cell Biol.2003.23(13):4559-72.
[28]Pearson EC, Bates DL, Prospero TD, Thomas JO. Neuronal nuclei and glial nuclei from mammalian cerebral cortex. Nucleosome repeat lengths. DNA contents and HI contents. Eur J Biochem.1984.144(2):353-60.
[29]Fan Y, Nikitina T, Zhao J. et al. Histone HI depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell.2005.123(7):1199-212.
[30]Pennings S, Meersseman G, Bradbury EM. Linker histones HI and H5 prevent the mobility of positioned nucleosomes. Proc Natl Acad Sci U S A.1994.91(22):10275-9.
[31]Routh A, Sandin S, Rhodes D. Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure. Proc Natl Acad Sci U S A.2008.105(26):8872-7.
[32]Bates DL, Butler PJ, Pearson EC, Thomas JO. Stability of the higher-order structure of chicken-erythrocyte chromatin in solution. Eur J Biochem.1981.119(3):469-76.
[33]Fan Y, Nikitina T, Zhao J. et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell.2005.123(7):1199-212.
[34]Varga-Weisz PD, Becker PB. Regulation of higher-order chromatin structures by nucleosome-remodelling factors. Curr Opin Genet Dev.2006.16(2):151-6.
[35]Li G, Margueron R. Hu G, Stokes D. Wang YH, Reinberg D. Highly compacted chromatin formed in vitro reflects the dynamics of transcription activation in vivo. Mol Cell.2010.38(1):41-53.
[36]Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science.2006.311(5762):844-7.
[37]Ahringer J. NuRD and SIN3 histone deacetylase complexes in development. Trends Genet.2000.16(8):351-6.
[38]Wang HB, Zhang Y. Mi2, an auto-antigen for dermatomyositis. is an ATP-dependent nucleosome remodeling factor. Nucleic Acids Res.2001.29(12):2517-21.
[39]Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis.2003.20(1):19-24.
[40]Kapuscinski J. DAPI:a DNA-specific fluorescent probe. Biotech Histochem.1995.70(5):220-33.
[41]Kodiha M, Banski P, Stochaj U. Computer-based fluorescence quantification:a novel approach to study nucleolar biology. BMC Cell Biol.2011.12:25.
[42]Li DQ, Pakala SB, Nair SS, Eswaran J, Kumar R. Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. Cancer Res.2012.72(2):387-94.
[43]Thoma F, Koller T. Influence of histone H1 on chromatin structure. Cell.1977.12(1):101-7.
[44]Bustin M, Catez F. Lim JH. The dynamics of histone H1 function in chromatin. Mol Cell.2005.17(5):617-20.
[45]Catez F. Ueda T, Bustin M. Determinants of histone H1 mobility and chromatin binding in living cells. Nat Struct Mol Biol.2006.13(4):305-10.
[46]Maresca TJ, Freedman BS, Heald R. Histone H1 is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts. J Cell Biol.2005.169(6):859-69.
[47]Maresca TJ. Heald R. The long and the short of it:linker histone H1 is required for metaphase chromosome compaction. Cell Cycle.2006.5(6):589-91.
[48]Shen X, Yu L. Weir JW, Gorovsky MA. Linker histones are not essential and affect chromatin condensation in vivo. Cell.1995.82(1):47-56.
[49]Stoldt S. Wenzel D, Schulze E, Doenecke D, Happel N. G1 phase-dependent nucleolar accumulation of human histone Hlx. Biol Cell.2007.99(10):541-52.
[50]Misteli T, Gunjan A, Hock R. Bustin M, Brown DT. Dynamic binding of histone H1 to chromatin in living cells. Nature.2000.408(6814):877-81.
[51]Lever MA, Th'ng JP, Sun X, Hendzel MJ. Rapid exchange of histone H1. I on chromatin in living human cells. Nature.2000.408(6814):873-6.
[52]Shen X, Yu L, Weir JW, Gorovsky MA. Linker histones are not essential and affect chromatin condensation in vivo. Cell.1995.82(1):47-56.
[53]Balasenthil S, Gururaj AE, Talukder AH, et al. Identification of Pax5 as a target of MTA1 in B-cell lymphomas. Cancer Res.2007.67(15):7132-8.
[54]Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci U S A. 2006.103(17):6670-5.
[55]Pakala SB, Singh K, Reddy SD, et al. TGF-betal signaling targets metastasis-associated protein 1, a new-effector in epithelial cells. Oncogene.2011.
[56]Maresca TJ, Freedman BS, Heald R. Histone HI is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts. J Cell Biol.2005.169(6):859-69.
[57]Ohsumi K, Katagiri C, Kishimoto T. Chromosome condensation in Xenopus mitotic extracts without histone HI. Science.1993.262(5142):2033-5.
[58]Toh Y, Pencil SD. Nicolson GL. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mtal, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene.1995. 159(1):97-104.
[59]Li W, Zhang J, Liu X, Xu R, Zhang Y. Correlation of appearance of metastasis-associated protein 1 (Mtal) with spermatogenesis in developing mouse testis. Cell Tissue Res.2007.329(2):351-62.
[60]Li W, Liu XP, Xu RJ. Zhang YQ. Immunolocalization assessment of metastasis-associated protein 1 in human and mouse mature testes and its association with spermatogenesis. Asian J Androl.2007.9(3):345-52.
[61]Thakur MK, Ghosh S. Interaction of estrogen receptor alpha transactivation domain with MTA1 decreases in old mouse brain. J Mol Neurosci.2009.37(3):269-73.
[62]Li W, Zhu H, Bao W, et al. Involvement of metastasis tumor antigen 1 in hepatic regeneration and proliferation. Cell Physiol Biochem.2008.22(1-4):315-26.
[63]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTA1. a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[64]Manavathi B, Singh K, Kumar R. MTA family of coregulators in nuclear receptor biology and pathology. Nucl Recept Signal.2007.5:e010.
[65]Gaspar-Maia A, Alajem A, Meshorer E, Ramalho-Santos M. Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol.2011.12(1):36-47.
[66]Mattout A, Meshorer E. Chromatin plasticity and genome organization in pluripotent embryonic stem cells. Curr Opin Cell Biol.2010.22(3):334-41.
[67]Ahmed K, Dehghani H, Rugg-Gunn P, Fussner E, Rossant J. Bazett-Jones DP. Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo. PLOSONE.2010.5(5):e10531.
[68]Bhattacharya D. Talwar S, Mazumder A, Shivashankar GV. Spatio-temporal plasticity in chromatin organization in mouse cell differentiation and during Drosophila embryogenesis. Biophys J.2009.96(9): 3832-9.
[69]Meshorer E. Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol.2006.7(7):540-6.
[70]Campisi J. Aging, chromatin, and food restriction-connecting the dots. Science.2000.289(5487):2062-3.
[71]Gerlitz G, Hock R. Ueda T. Bustin M. The dynamics of HMG protein-chromatin interactions in living cells. Biochem Cell Biol.2009.87(1):127-37.
[72]Rochman M. Malicet C, Bustin M. HMGN5/NSBP1:a new member of the HMGN protein family that affects chromatin structure and function. Biochim Biophys Acta.2010.1799(1-2):86-92.
[73]Catez F, Yang H, Tracey KJ, Reeves R, Misteli T, Bustin M. Network of dynamic interactions between histone HI and high-mobility-group proteins in chromatin. Mol Cell Biol.2004.24(10):4321-8.
[74]Alami R, Fan Y, Pack S, et al. Mammalian linker-histone subtypes differentially affect gene expression in vivo. Proc Natl Acad Sci U S A.2003.100(10):5920-5.
[75]Shen X, Gorovsky MA. Linker histone H1 regulates specific gene expression but not global transcription in vivo. Cell.1996.86(3):475-83.
[76]Bharadwaj R, Yu H. The spindle checkpoint, aneuploidy, and cancer. Oncogene.2004.23(11):2016-27.
[77]Jallepalli PV, Lengauer C. Chromosome segregation and cancer:cutting through the mystery. Nat Rev Cancer. 2001.1(2):109-17.
[78]Hartwell LH, Weinert TA. Checkpoints:controls that ensure the order of cell cycle events. Science.1989. 246(4930):629-34.
[79]Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol.2007. 8(5):379-93.
[80]de Voer RM, Hoogerbrugge N, Kuiper RP. Spindle-assembly checkpoint and gastrointestinal cancer. N Engl J Med.2011.364(13):1279-80.
[81]Lengauer C, Wang Z. From spindle checkpoint to cancer. Nat Genet.2004.36(11):1144-5.
[82]Burke DJ, Stukenberg PT. Linking kinetochore-microtubule binding to the spindle checkpoint. Dev Cell.2008. 14(4):474.9.
[83]Hoyt MA. A new view of the spindle checkpoint. J Cell Biol.2001.154(5):909-11.
[84]Bharadwaj R, Yu H. The spindle checkpoint, aneuploidy, and cancer. Oncogene.2004.23(11):2016-27.
[85]Li R, Murray AW. Feedback control of mitosis in budding yeast. Cell.1991.66(3):519-31.
[86]Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell.1991.66(3):507-17.
[87]Musacchio A. Spindle assembly checkpoint:the third decade. Philos Trans R Soc Lond B Biol Sci.2011. 366(1584):3595-604.
[88]Wassmann K, Benezra R. Mitotic checkpoints:from yeast to cancer. Curr Opin Genet Dev.2001.11(1):83-90.
[89]Belgareh N, Rabut G, Bai SW, et al. An evolutionarily conserved NPC subcomplex, which redistributes in part to kinetochores in mammalian cells. J Cell Biol.2001.154(6):1147-60.
[90]Joseph J, Tan SH, Karpova TS, McNally JG, Dasso M. SUMO-1 targets RanGAPl to kinetochores and mitotic spindles. J Cell Biol.2002.156(4):595-602.
[91]Salina D, Enarson P, Rattner JB, Burke B. Nup358 integrates nuclear envelope breakdown with kinetochore assembly. J Cell Biol.2003.162(6):991-1001.
[92]Niepel M. Strambio-de-Castillia C, Fasolo J, Chait BT, Rout MP. The nuclear pore complex-associated protein, Mlp2p, binds to the yeast spindle pole body and promotes its efficient assembly. J Cell Biol.2005.170(2): 225-35.
[93]Galy V, Askjaer P, Franz C, Lopez-Iglesias C, Mattaj IW. MEL-28, a novel nuclear-envelope and kinetochore protein essential for zygotic nuclear-envelope assembly in C. elegans. Curr Biol.2006.16(17):1748-56.
[94]Orjalo AV, Arnaoutov A, Shen Z, et al. The Nup107-160 nucleoporin complex is required for correct bipolar spindle assembly. Mol Biol Cell.2006.17(9):3806-18.
[95]Guttinger S, Laurell E, Kutay U. Orchestrating nuclear envelope disassembly and reassembly during mitosis. Nat Rev Mol Cell Biol.2009.10(3):178-91.
[96]Nakano H, Funasaka T, Hashizume C, Wong RW. Nucleoporin translocated promoter region (Tpr) associates with dynein complex, preventing chromosome lagging formation during mitosis. J Biol Chem.2010.285(14): 10841-9.
[97]Terry LJ. Shows EB, Wente SR. Crossing the nuclear envelope:hierarchical regulation of nucleocytoplasmic transport. Science.2007.318(5855):1412-6.
[98]Wang X, Babu JR, Harden JM, et al. The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem.2001.276(28): 26559-67.
[99]Babu JR. Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van DJM. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol.2003.160(3):341-53.
[100]Lee SH, Sterling H. Burlingame A. McCormick F. Tpr directly binds to Mad1 and Mad2 and is important for the Mad 1-Mad2-mediated mitotic spindle checkpoint. Genes Dev.2008.22(21):2926-31.
[101]Iouk T, Kerscher O, Scott RJ, Basrai MA, Wozniak RW. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. J Cell Biol.2002.159(5):807-19.
[102]Qi H, Rath U, Wang D, et al. Megator, an essential coiled-coil protein that localizes to the putative spindle matrix during mitosis in Drosophila. Mo1 Biol Cell.2004.15(11):4854-65.
[103]Lince-Faria M, Maffini S, Orr B, et al. Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator. J Cell Biol.2009.184(5):647-57.
[104]Luo X, Tang Z, Xia G et al. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mo1 Biol.2004.11(4):338-45.
[105]De Antoni A, Pearson CG, Cimini D, et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol.2005.15(3):214-25.
[106]Boisvert FM, van KS, Navascues J, Lamond Al. The multifunctional nucleolus. Nat Rev Mol Cell Biol.2007. 8(7):574-85.
[107]Lischwe MA, Ochs RL, Reddy R, et al. Purification and partial characterization of a nucleolar scleroderma antigen (Mr=34,000; pI,8.5) rich in NQNG-dimethylarginine. J Biol Chem.1985.260(26):14304-10.
[108]Tajrishi MM, Tuteja R. Tuteja N. Nucleolin:The most abundant multifunctional phosphoprotein of nucleolus. Commun Integr Bio1.2011.4(3):267-75.
[109]Hernandez-Verdun D. The nucleolus today. J Cell Sci.1991.99 (Pt 3):465-71.
[110]Zhou Y, King ML. Sending RNAs into the future:RNA localization and germ cell fate. IUBMB Life.2004. 56(1):19-27.
[111]Jansen RP. mRNA localization:message on the move. Nat Rev Mol Cell Biol.2001.2(4):247-56.
[112]Thomas MG, Martinez TLJ, Loschi M, et al. Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes. Mol Biol Cell.2005.16(1):405-20.
[113]Atkinson SJ. Doberstein SK, Pollard TD. Moving off the beaten track. Curr Biol.1992.2(6):326-8.
[114]Kedersha N, Anderson P. Mammalian stress granules and processing bodies. Methods Enzymol.2007.431: 61-81.
[115]Buchan JR, Parker R. Eukaryotic stress granules:the ins and outs of translation. Mol Cell.2009.36(6):932-41.
[116]Anderson P, Kedersha N. RNA granules. J Cell Biol.2006.172(6):803-8.
[117]Ivanov PA, Nadezhdina ES. [Stress granules:RNP-containing cytoplasmic bodies springing up under stress. The structure and mechanism of organization]. Mol Biol (Mosk).2006.40(6):937-44.
[118]Hua Y, Zhou J. Survival motor neuron protein facilitates assembly of stress granules. FEBS Lett.2004. 572(1-3):69-74.
[1]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat.1993.25(2):165-74.
[2]Toh Y. Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mtal, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem.1994.269(37):22958-63.
[3]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mtal, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene.1995. 159(1):97-104.
[4]Kumar R, Wang RA, Bagheri-Yarmand R. Emerging roles of MTA family members in human cancers. Semin Oncol.2003.30(5 Suppl 16):30-7.
[5]Herman MA, Ch'ng Q, Hettenbach SM, Ratliff TM, Kenyon C. Herman RK. EGL-27 is similar to a metastasis-associated factor and controls cell polarity and cell migration in C. elegans. Development.1999. 126(5):1055-64.
[6]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTA1, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[7]Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers:molecular functions and clinical implications. Clin Exp Metastasis.2009.26(3):215-27.
[8]Simpson A, Uitto J, Rodeck U, Mahoney MG Differential expression and subcellular distribution of the mouse metastasis-associated proteins Mtal and Mta3. Gene.2001.273(1):29-39.
[9]Manavathi B. Kumar R. Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem.2007.282(3):1529-33.
[10]Goodwin GH, Nicolas RH. The BAH domain, polybromo and the RSC chromatin remodelling complex. Gene. 2001.268(1-2):1-7.
[11]Oliver AW, Jones SA, Roe SM. Matthews S, Goodwin GH, Pearl LH. Crystal structure of the proximal BAH domain of the polybromo protein. Biochem J.2005.389(Pt 3):657-64.
[12]Aramaki Y, Ogawa K, Toh Y, et al. Direct interaction between metastasis-associated protein 1 and endophilin 3. FEBS Lett. 2005.579(17):3731-6.
[13]Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci U S A.2006.103(17):6670-5.
[14]Li W, Ma L, Zhao J, Liu X, Li Z, Zhang Y Expression profile of MTA1 in adult mouse tissues. Tissue Cell. 2009.41(6):390-9.
[15]Nawa A, Nishimori K, Lin P, et al. Tumor metastasis-associated human MTA1 gene:its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J Cell Biochem.2000.79(2):202-12.
[16]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol.2004.35(4):424-9.
[17]Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol.2006.37(6):656-61.
[18]Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas:correlation with invasion and metastasis. Int J Cancer.1997.74(4):459-63.
[19]Deng X, Du L, Wang C, et al. Close Association of Metastasis-Associated Protein 1 Overexpression with Increased Angiogenesis and Poor Survival in Patients with Histologically Node-Negative Gastric Cancer. World ISurg.2013.
[20]Martin MD, Hilsenbeck SG, Mohsin SK, et al. Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. Breast Cancer Res Treat.2006.95(1):7-12.
[21]Cheng CW, Liu YF, Yu JC, et al. Prognostic Significance of cyclin Dl, beta-catenin. and MTA1 in Patients with Invasive Ductal Carcinoma of the Breast. Ann Surg Oncol.2012.
[22]Toh Y, Kuwano H, Mori M, Nicolson GL, Sugimachi K. Overexpression of metastasis-associated MTAI mRNAin invasive oesophageal carcinomas. Br J Cancer.1999.79(11-12):1723-6.
[23]Sasaki H, Moriyama S, Nakashima Y, et al. Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer.2002.35(2):149-54.
[24]Kawasaki G, Yanamoto S, Yoshitomi I, Yamada S, Mizuno A. Overexpression of metastasis-associated MTA1 in oral squamous cell carcinomas:correlation with metastasis and invasion. Int J Oral Maxillofac Surg.2008. 37(11):1039-46.
[25]Hamatsu T, Rikimaru T, Yamashita Y, et al. The role of MTA1 gene expression in human hepatocellular carcinoma. Oncol Rep.2003.10(3):599-604.
[26]Ryu SH, Chung YH, Lee H, et al. Metastatic tumor antigen I is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma. Hepatology.2008.47(3):929-36.
[27]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol.2004.35(4):424-9.
[28]Li W, Zhang J. Liu X, Xu R, Zhang Y. Correlation of appearance of metastasis-associated proteinl (Mtal) with spermatogenesis in developing mouse testis. Cell Tissue Res.2007.329(2):351-62.
[29]Li W, Liu XP, Xu RJ. Zhang YQ. Immunolocalization assessment of metastasis-associated protein 1 in human and mouse mature testes and its association with spermatogenesis. Asian J Androl.2007.9(3):345-52.
[30]Thakur MK, Ghosh S. Interaction of estrogen receptor alpha transactivation domain with MTAI decreases in old mouse brain. J Mol Neurosci.2009.37(3):269-73.
[31]Manavathi B. Peng S, Rayala SK, et al. Repression of Six3 by a corepressor regulates rhodopsin expression. Proc Natl Acad Sci U S A.2007.104(32):13128-33.
[32]Li W, Zhu H, Bao W, et al. Involvement of metastasis tumor antigen 1 in hepatic regeneration and proliferation. Cell Physiol Biochem.2008.22(1-4):315-26.
[33]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTAI, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[34]Chen Z, Han M. Role of C. elegans lin-40 MTA in vulval fate specification and morphogenesis. Development. 2001.128(23):4911-21.
[35]Singh RR, Kumar R. MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer. J Mammary Gland Biol Neoplasia.2007.12(2-3):115-25.
[36]Salot S, Gude R. MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. Eur J Cancer. 2013.49(2):492-9.
[37]Salot S, Gude R. MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. Eur J Cancer. 2012.
[38]Mazumdar A, Wang RA, Mishra SK, et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol.2001.3(1):30-7.
[39]Balasenthil S, Gururaj AE, Talukder AH, et al. Identification of Pax5 as a target of MTAI in B-cell lymphomas. Cancer Res.2007.67(15):7132-8.
[40]Pakala SB, Singh K, Reddy SD. et al. TGF-betal signaling targets metastasis-associated protein 1, a new effector in epithelial cells. Oncogene.2011.
[41]Sankaran D, Pakala SB, Nair VS. et al. Mechanism of MTA1 protein overexpression-linked invasion:MTA1 regulation of hyaluronan-mediated motility receptor (HMMR) expression and function. J Biol Chem.2012. 287(8):5483-91.
[42]Li DQ, Pakala SB. Nair SS, Eswaran J. Kumar R. Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. Cancer Res.2012.72(2):387-94.
[2]Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mtal, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem.1994.269(37):22958-63.
[3]Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers:molecular functions and clinical implications. Clin Exp Metastasis.2009.26(3):215-27.
[4]Li W, Ma L, Zhao J, Liu X, Li Z, Zhang Y Expression profile of MTA1 in adult mouse tissues. Tissue Cell. 2009.41(6):390-9.
[5]Kumar R, Wang RA, Bagheri-Yarmand R. Emerging roles of MTA family members in human cancers. Semin Oncol.2003.30(5 Suppl 16):30-7.
[6]Manavathi B, Kumar R. Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem.2007.282(3):1529-33.
[7]Simpson A, Uitto J, Rodeck U, Mahoney MG. Differential expression and subcellular distribution of the mouse metastasis-associated proteins Mtal and Mta3. Gene.2001.273(1):29-39.
[8]Nawa A, Nishimori K, Lin P, et al. Tumor metastasis-associated human MTA1 gene:its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J CellBiochem.2000.79(2):202-12.
[9]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha Hum Pathol.2004.35(4):424-9.
[10]Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol.2006.37(6):656-61.
[11]Rajendra TK, Gonsalvez GB, Walker MP, Shpargel KB, Salz HK, Matera AG A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol.2007.176(6): 831-41.
[12]Walker MP, Rajendra TK, Saieva L, Fuentes JL, Pellizzoni L, Matera AG. SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain. Hurn Mo1 Genet.2008,17(21):3399-410.
[13]Lunn MR, Wang CH. Spinal muscular atrophy. Lancet.2008.371(9630):2120-33.
[14]Burghes AH, Beattie CE. Spinal muscular atrophy:why do low levels of survival motor neuron protein make motor neurons sick. Nat Rev Neurosci.2009.10(8):597-609.
[15]Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell.1998.2(6):851-61.
[16]Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature.1997.389(6648):251-60.
[17]Tremethick DJ. Higher-order structures of chromatin:the elusive 30 nm fiber. Cell.2007.128(4):6514.
[18]Horn PJ, Peterson CL. Molecular biology. Chromatin higher order folding--wrapping up transcription. Science. 2002.297(5588):1824-7.
[19]Carruthers LM, Bednar J, Woodcock CL, Hansen JC. Linker histones stabilize the intrinsic salt-dependent folding of nucleosomal arrays:mechanistic ramifications for higher-order chromatin folding. Biochemistry. 1998.37(42):14776-87.
[20]Thoma F, Koller T, Klug A. Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin. J Cell Biol.1979.83(2 Pt 1):403-27.
[21]Hizume K, Yoshimura SH. Takeyasu K. Linker histone H1 per se can induce three-dimensional folding of chromatin fiber. Biochemistry.2005.44(39):12978-89.
[22]Hamiche A, Schultz P, Ramakrishnan V. Oudet P, Prunell A. Linker histone-dependent DNA structure in linear mononucleosomes. J Mol Biol.1996.257(1):30-42.
[23]Bednar J, Horowitz RA, Grigoryev SA, et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc Natl Acad Sci U S A. 1998.95(24):14173-8.
[24]Allan J, Hartman PG Crane-Robinson C. Aviles FX. The structure of histone H1 and its location in chromatin. Nature.1980.288(5792):675-9.
[25]Travers A. The location of the linker histone on the nucleosome. Trends Biochem Sci.1999.24(1):4-7.
[26]Woodcock CL, Skoultchi AI, Fan Y. Role of linker histone in chromatin structure and function:H1 stoichiometry and nucleosome repeat length. Chromosome Res.2006.14(1):17-25.
[27]Fan Y, Nikitina T, Morin-Kensicki EM. et al. H1 linker histones are essential for mouse development and affect nucleosome spacing in vivo. Mo1 Cell Biol.2003.23(13):4559-72.
[28]Pearson EC, Bates DL, Prospero TD, Thomas JO. Neuronal nuclei and glial nuclei from mammalian cerebral cortex. Nucleosome repeat lengths. DNA contents and HI contents. Eur J Biochem.1984.144(2):353-60.
[29]Fan Y, Nikitina T, Zhao J. et al. Histone HI depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell.2005.123(7):1199-212.
[30]Pennings S, Meersseman G, Bradbury EM. Linker histones HI and H5 prevent the mobility of positioned nucleosomes. Proc Natl Acad Sci U S A.1994.91(22):10275-9.
[31]Routh A, Sandin S, Rhodes D. Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure. Proc Natl Acad Sci U S A.2008.105(26):8872-7.
[32]Bates DL, Butler PJ, Pearson EC, Thomas JO. Stability of the higher-order structure of chicken-erythrocyte chromatin in solution. Eur J Biochem.1981.119(3):469-76.
[33]Fan Y, Nikitina T, Zhao J. et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell.2005.123(7):1199-212.
[34]Varga-Weisz PD, Becker PB. Regulation of higher-order chromatin structures by nucleosome-remodelling factors. Curr Opin Genet Dev.2006.16(2):151-6.
[35]Li G, Margueron R. Hu G, Stokes D. Wang YH, Reinberg D. Highly compacted chromatin formed in vitro reflects the dynamics of transcription activation in vivo. Mol Cell.2010.38(1):41-53.
[36]Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science.2006.311(5762):844-7.
[37]Ahringer J. NuRD and SIN3 histone deacetylase complexes in development. Trends Genet.2000.16(8):351-6.
[38]Wang HB, Zhang Y. Mi2, an auto-antigen for dermatomyositis. is an ATP-dependent nucleosome remodeling factor. Nucleic Acids Res.2001.29(12):2517-21.
[39]Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis.2003.20(1):19-24.
[40]Kapuscinski J. DAPI:a DNA-specific fluorescent probe. Biotech Histochem.1995.70(5):220-33.
[41]Kodiha M, Banski P, Stochaj U. Computer-based fluorescence quantification:a novel approach to study nucleolar biology. BMC Cell Biol.2011.12:25.
[42]Li DQ, Pakala SB, Nair SS, Eswaran J, Kumar R. Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. Cancer Res.2012.72(2):387-94.
[43]Thoma F, Koller T. Influence of histone H1 on chromatin structure. Cell.1977.12(1):101-7.
[44]Bustin M, Catez F. Lim JH. The dynamics of histone H1 function in chromatin. Mol Cell.2005.17(5):617-20.
[45]Catez F. Ueda T, Bustin M. Determinants of histone H1 mobility and chromatin binding in living cells. Nat Struct Mol Biol.2006.13(4):305-10.
[46]Maresca TJ, Freedman BS, Heald R. Histone H1 is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts. J Cell Biol.2005.169(6):859-69.
[47]Maresca TJ. Heald R. The long and the short of it:linker histone H1 is required for metaphase chromosome compaction. Cell Cycle.2006.5(6):589-91.
[48]Shen X, Yu L. Weir JW, Gorovsky MA. Linker histones are not essential and affect chromatin condensation in vivo. Cell.1995.82(1):47-56.
[49]Stoldt S. Wenzel D, Schulze E, Doenecke D, Happel N. G1 phase-dependent nucleolar accumulation of human histone Hlx. Biol Cell.2007.99(10):541-52.
[50]Misteli T, Gunjan A, Hock R. Bustin M, Brown DT. Dynamic binding of histone H1 to chromatin in living cells. Nature.2000.408(6814):877-81.
[51]Lever MA, Th'ng JP, Sun X, Hendzel MJ. Rapid exchange of histone H1. I on chromatin in living human cells. Nature.2000.408(6814):873-6.
[52]Shen X, Yu L, Weir JW, Gorovsky MA. Linker histones are not essential and affect chromatin condensation in vivo. Cell.1995.82(1):47-56.
[53]Balasenthil S, Gururaj AE, Talukder AH, et al. Identification of Pax5 as a target of MTA1 in B-cell lymphomas. Cancer Res.2007.67(15):7132-8.
[54]Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci U S A. 2006.103(17):6670-5.
[55]Pakala SB, Singh K, Reddy SD, et al. TGF-betal signaling targets metastasis-associated protein 1, a new-effector in epithelial cells. Oncogene.2011.
[56]Maresca TJ, Freedman BS, Heald R. Histone HI is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts. J Cell Biol.2005.169(6):859-69.
[57]Ohsumi K, Katagiri C, Kishimoto T. Chromosome condensation in Xenopus mitotic extracts without histone HI. Science.1993.262(5142):2033-5.
[58]Toh Y, Pencil SD. Nicolson GL. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mtal, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene.1995. 159(1):97-104.
[59]Li W, Zhang J, Liu X, Xu R, Zhang Y. Correlation of appearance of metastasis-associated protein 1 (Mtal) with spermatogenesis in developing mouse testis. Cell Tissue Res.2007.329(2):351-62.
[60]Li W, Liu XP, Xu RJ. Zhang YQ. Immunolocalization assessment of metastasis-associated protein 1 in human and mouse mature testes and its association with spermatogenesis. Asian J Androl.2007.9(3):345-52.
[61]Thakur MK, Ghosh S. Interaction of estrogen receptor alpha transactivation domain with MTA1 decreases in old mouse brain. J Mol Neurosci.2009.37(3):269-73.
[62]Li W, Zhu H, Bao W, et al. Involvement of metastasis tumor antigen 1 in hepatic regeneration and proliferation. Cell Physiol Biochem.2008.22(1-4):315-26.
[63]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTA1. a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[64]Manavathi B, Singh K, Kumar R. MTA family of coregulators in nuclear receptor biology and pathology. Nucl Recept Signal.2007.5:e010.
[65]Gaspar-Maia A, Alajem A, Meshorer E, Ramalho-Santos M. Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol.2011.12(1):36-47.
[66]Mattout A, Meshorer E. Chromatin plasticity and genome organization in pluripotent embryonic stem cells. Curr Opin Cell Biol.2010.22(3):334-41.
[67]Ahmed K, Dehghani H, Rugg-Gunn P, Fussner E, Rossant J. Bazett-Jones DP. Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo. PLOSONE.2010.5(5):e10531.
[68]Bhattacharya D. Talwar S, Mazumder A, Shivashankar GV. Spatio-temporal plasticity in chromatin organization in mouse cell differentiation and during Drosophila embryogenesis. Biophys J.2009.96(9): 3832-9.
[69]Meshorer E. Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol.2006.7(7):540-6.
[70]Campisi J. Aging, chromatin, and food restriction-connecting the dots. Science.2000.289(5487):2062-3.
[71]Gerlitz G, Hock R. Ueda T. Bustin M. The dynamics of HMG protein-chromatin interactions in living cells. Biochem Cell Biol.2009.87(1):127-37.
[72]Rochman M. Malicet C, Bustin M. HMGN5/NSBP1:a new member of the HMGN protein family that affects chromatin structure and function. Biochim Biophys Acta.2010.1799(1-2):86-92.
[73]Catez F, Yang H, Tracey KJ, Reeves R, Misteli T, Bustin M. Network of dynamic interactions between histone HI and high-mobility-group proteins in chromatin. Mol Cell Biol.2004.24(10):4321-8.
[74]Alami R, Fan Y, Pack S, et al. Mammalian linker-histone subtypes differentially affect gene expression in vivo. Proc Natl Acad Sci U S A.2003.100(10):5920-5.
[75]Shen X, Gorovsky MA. Linker histone H1 regulates specific gene expression but not global transcription in vivo. Cell.1996.86(3):475-83.
[76]Bharadwaj R, Yu H. The spindle checkpoint, aneuploidy, and cancer. Oncogene.2004.23(11):2016-27.
[77]Jallepalli PV, Lengauer C. Chromosome segregation and cancer:cutting through the mystery. Nat Rev Cancer. 2001.1(2):109-17.
[78]Hartwell LH, Weinert TA. Checkpoints:controls that ensure the order of cell cycle events. Science.1989. 246(4930):629-34.
[79]Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol.2007. 8(5):379-93.
[80]de Voer RM, Hoogerbrugge N, Kuiper RP. Spindle-assembly checkpoint and gastrointestinal cancer. N Engl J Med.2011.364(13):1279-80.
[81]Lengauer C, Wang Z. From spindle checkpoint to cancer. Nat Genet.2004.36(11):1144-5.
[82]Burke DJ, Stukenberg PT. Linking kinetochore-microtubule binding to the spindle checkpoint. Dev Cell.2008. 14(4):474.9.
[83]Hoyt MA. A new view of the spindle checkpoint. J Cell Biol.2001.154(5):909-11.
[84]Bharadwaj R, Yu H. The spindle checkpoint, aneuploidy, and cancer. Oncogene.2004.23(11):2016-27.
[85]Li R, Murray AW. Feedback control of mitosis in budding yeast. Cell.1991.66(3):519-31.
[86]Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell.1991.66(3):507-17.
[87]Musacchio A. Spindle assembly checkpoint:the third decade. Philos Trans R Soc Lond B Biol Sci.2011. 366(1584):3595-604.
[88]Wassmann K, Benezra R. Mitotic checkpoints:from yeast to cancer. Curr Opin Genet Dev.2001.11(1):83-90.
[89]Belgareh N, Rabut G, Bai SW, et al. An evolutionarily conserved NPC subcomplex, which redistributes in part to kinetochores in mammalian cells. J Cell Biol.2001.154(6):1147-60.
[90]Joseph J, Tan SH, Karpova TS, McNally JG, Dasso M. SUMO-1 targets RanGAPl to kinetochores and mitotic spindles. J Cell Biol.2002.156(4):595-602.
[91]Salina D, Enarson P, Rattner JB, Burke B. Nup358 integrates nuclear envelope breakdown with kinetochore assembly. J Cell Biol.2003.162(6):991-1001.
[92]Niepel M. Strambio-de-Castillia C, Fasolo J, Chait BT, Rout MP. The nuclear pore complex-associated protein, Mlp2p, binds to the yeast spindle pole body and promotes its efficient assembly. J Cell Biol.2005.170(2): 225-35.
[93]Galy V, Askjaer P, Franz C, Lopez-Iglesias C, Mattaj IW. MEL-28, a novel nuclear-envelope and kinetochore protein essential for zygotic nuclear-envelope assembly in C. elegans. Curr Biol.2006.16(17):1748-56.
[94]Orjalo AV, Arnaoutov A, Shen Z, et al. The Nup107-160 nucleoporin complex is required for correct bipolar spindle assembly. Mol Biol Cell.2006.17(9):3806-18.
[95]Guttinger S, Laurell E, Kutay U. Orchestrating nuclear envelope disassembly and reassembly during mitosis. Nat Rev Mol Cell Biol.2009.10(3):178-91.
[96]Nakano H, Funasaka T, Hashizume C, Wong RW. Nucleoporin translocated promoter region (Tpr) associates with dynein complex, preventing chromosome lagging formation during mitosis. J Biol Chem.2010.285(14): 10841-9.
[97]Terry LJ. Shows EB, Wente SR. Crossing the nuclear envelope:hierarchical regulation of nucleocytoplasmic transport. Science.2007.318(5855):1412-6.
[98]Wang X, Babu JR, Harden JM, et al. The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem.2001.276(28): 26559-67.
[99]Babu JR. Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van DJM. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol.2003.160(3):341-53.
[100]Lee SH, Sterling H. Burlingame A. McCormick F. Tpr directly binds to Mad1 and Mad2 and is important for the Mad 1-Mad2-mediated mitotic spindle checkpoint. Genes Dev.2008.22(21):2926-31.
[101]Iouk T, Kerscher O, Scott RJ, Basrai MA, Wozniak RW. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. J Cell Biol.2002.159(5):807-19.
[102]Qi H, Rath U, Wang D, et al. Megator, an essential coiled-coil protein that localizes to the putative spindle matrix during mitosis in Drosophila. Mo1 Biol Cell.2004.15(11):4854-65.
[103]Lince-Faria M, Maffini S, Orr B, et al. Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator. J Cell Biol.2009.184(5):647-57.
[104]Luo X, Tang Z, Xia G et al. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mo1 Biol.2004.11(4):338-45.
[105]De Antoni A, Pearson CG, Cimini D, et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol.2005.15(3):214-25.
[106]Boisvert FM, van KS, Navascues J, Lamond Al. The multifunctional nucleolus. Nat Rev Mol Cell Biol.2007. 8(7):574-85.
[107]Lischwe MA, Ochs RL, Reddy R, et al. Purification and partial characterization of a nucleolar scleroderma antigen (Mr=34,000; pI,8.5) rich in NQNG-dimethylarginine. J Biol Chem.1985.260(26):14304-10.
[108]Tajrishi MM, Tuteja R. Tuteja N. Nucleolin:The most abundant multifunctional phosphoprotein of nucleolus. Commun Integr Bio1.2011.4(3):267-75.
[109]Hernandez-Verdun D. The nucleolus today. J Cell Sci.1991.99 (Pt 3):465-71.
[110]Zhou Y, King ML. Sending RNAs into the future:RNA localization and germ cell fate. IUBMB Life.2004. 56(1):19-27.
[111]Jansen RP. mRNA localization:message on the move. Nat Rev Mol Cell Biol.2001.2(4):247-56.
[112]Thomas MG, Martinez TLJ, Loschi M, et al. Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes. Mol Biol Cell.2005.16(1):405-20.
[113]Atkinson SJ. Doberstein SK, Pollard TD. Moving off the beaten track. Curr Biol.1992.2(6):326-8.
[114]Kedersha N, Anderson P. Mammalian stress granules and processing bodies. Methods Enzymol.2007.431: 61-81.
[115]Buchan JR, Parker R. Eukaryotic stress granules:the ins and outs of translation. Mol Cell.2009.36(6):932-41.
[116]Anderson P, Kedersha N. RNA granules. J Cell Biol.2006.172(6):803-8.
[117]Ivanov PA, Nadezhdina ES. [Stress granules:RNP-containing cytoplasmic bodies springing up under stress. The structure and mechanism of organization]. Mol Biol (Mosk).2006.40(6):937-44.
[118]Hua Y, Zhou J. Survival motor neuron protein facilitates assembly of stress granules. FEBS Lett.2004. 572(1-3):69-74.
[1]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res Treat.1993.25(2):165-74.
[2]Toh Y. Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mtal, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem.1994.269(37):22958-63.
[3]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel metastasis-associated candidate gene, mtal, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene.1995. 159(1):97-104.
[4]Kumar R, Wang RA, Bagheri-Yarmand R. Emerging roles of MTA family members in human cancers. Semin Oncol.2003.30(5 Suppl 16):30-7.
[5]Herman MA, Ch'ng Q, Hettenbach SM, Ratliff TM, Kenyon C. Herman RK. EGL-27 is similar to a metastasis-associated factor and controls cell polarity and cell migration in C. elegans. Development.1999. 126(5):1055-64.
[6]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTA1, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[7]Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers:molecular functions and clinical implications. Clin Exp Metastasis.2009.26(3):215-27.
[8]Simpson A, Uitto J, Rodeck U, Mahoney MG Differential expression and subcellular distribution of the mouse metastasis-associated proteins Mtal and Mta3. Gene.2001.273(1):29-39.
[9]Manavathi B. Kumar R. Metastasis tumor antigens, an emerging family of multifaceted master coregulators. J Biol Chem.2007.282(3):1529-33.
[10]Goodwin GH, Nicolas RH. The BAH domain, polybromo and the RSC chromatin remodelling complex. Gene. 2001.268(1-2):1-7.
[11]Oliver AW, Jones SA, Roe SM. Matthews S, Goodwin GH, Pearl LH. Crystal structure of the proximal BAH domain of the polybromo protein. Biochem J.2005.389(Pt 3):657-64.
[12]Aramaki Y, Ogawa K, Toh Y, et al. Direct interaction between metastasis-associated protein 1 and endophilin 3. FEBS Lett. 2005.579(17):3731-6.
[13]Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci U S A.2006.103(17):6670-5.
[14]Li W, Ma L, Zhao J, Liu X, Li Z, Zhang Y Expression profile of MTA1 in adult mouse tissues. Tissue Cell. 2009.41(6):390-9.
[15]Nawa A, Nishimori K, Lin P, et al. Tumor metastasis-associated human MTA1 gene:its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J Cell Biochem.2000.79(2):202-12.
[16]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol.2004.35(4):424-9.
[17]Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol.2006.37(6):656-61.
[18]Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas:correlation with invasion and metastasis. Int J Cancer.1997.74(4):459-63.
[19]Deng X, Du L, Wang C, et al. Close Association of Metastasis-Associated Protein 1 Overexpression with Increased Angiogenesis and Poor Survival in Patients with Histologically Node-Negative Gastric Cancer. World ISurg.2013.
[20]Martin MD, Hilsenbeck SG, Mohsin SK, et al. Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. Breast Cancer Res Treat.2006.95(1):7-12.
[21]Cheng CW, Liu YF, Yu JC, et al. Prognostic Significance of cyclin Dl, beta-catenin. and MTA1 in Patients with Invasive Ductal Carcinoma of the Breast. Ann Surg Oncol.2012.
[22]Toh Y, Kuwano H, Mori M, Nicolson GL, Sugimachi K. Overexpression of metastasis-associated MTAI mRNAin invasive oesophageal carcinomas. Br J Cancer.1999.79(11-12):1723-6.
[23]Sasaki H, Moriyama S, Nakashima Y, et al. Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer.2002.35(2):149-54.
[24]Kawasaki G, Yanamoto S, Yoshitomi I, Yamada S, Mizuno A. Overexpression of metastasis-associated MTA1 in oral squamous cell carcinomas:correlation with metastasis and invasion. Int J Oral Maxillofac Surg.2008. 37(11):1039-46.
[25]Hamatsu T, Rikimaru T, Yamashita Y, et al. The role of MTA1 gene expression in human hepatocellular carcinoma. Oncol Rep.2003.10(3):599-604.
[26]Ryu SH, Chung YH, Lee H, et al. Metastatic tumor antigen I is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma. Hepatology.2008.47(3):929-36.
[27]Moon WS, Chang K, Tarnawski AS. Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol.2004.35(4):424-9.
[28]Li W, Zhang J. Liu X, Xu R, Zhang Y. Correlation of appearance of metastasis-associated proteinl (Mtal) with spermatogenesis in developing mouse testis. Cell Tissue Res.2007.329(2):351-62.
[29]Li W, Liu XP, Xu RJ. Zhang YQ. Immunolocalization assessment of metastasis-associated protein 1 in human and mouse mature testes and its association with spermatogenesis. Asian J Androl.2007.9(3):345-52.
[30]Thakur MK, Ghosh S. Interaction of estrogen receptor alpha transactivation domain with MTAI decreases in old mouse brain. J Mol Neurosci.2009.37(3):269-73.
[31]Manavathi B. Peng S, Rayala SK, et al. Repression of Six3 by a corepressor regulates rhodopsin expression. Proc Natl Acad Sci U S A.2007.104(32):13128-33.
[32]Li W, Zhu H, Bao W, et al. Involvement of metastasis tumor antigen 1 in hepatic regeneration and proliferation. Cell Physiol Biochem.2008.22(1-4):315-26.
[33]Solari F, Bateman A, Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTAI, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development.1999.126(11):2483-94.
[34]Chen Z, Han M. Role of C. elegans lin-40 MTA in vulval fate specification and morphogenesis. Development. 2001.128(23):4911-21.
[35]Singh RR, Kumar R. MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer. J Mammary Gland Biol Neoplasia.2007.12(2-3):115-25.
[36]Salot S, Gude R. MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. Eur J Cancer. 2013.49(2):492-9.
[37]Salot S, Gude R. MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. Eur J Cancer. 2012.
[38]Mazumdar A, Wang RA, Mishra SK, et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol.2001.3(1):30-7.
[39]Balasenthil S, Gururaj AE, Talukder AH, et al. Identification of Pax5 as a target of MTAI in B-cell lymphomas. Cancer Res.2007.67(15):7132-8.
[40]Pakala SB, Singh K, Reddy SD. et al. TGF-betal signaling targets metastasis-associated protein 1, a new effector in epithelial cells. Oncogene.2011.
[41]Sankaran D, Pakala SB, Nair VS. et al. Mechanism of MTA1 protein overexpression-linked invasion:MTA1 regulation of hyaluronan-mediated motility receptor (HMMR) expression and function. J Biol Chem.2012. 287(8):5483-91.
[42]Li DQ, Pakala SB. Nair SS, Eswaran J. Kumar R. Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer. Cancer Res.2012.72(2):387-94.