RNA结合蛋白QKI在化疗药物诱导的肿瘤细胞凋亡过程中的作用及其机制研究
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摘要
细胞凋亡是机体细胞在正常生理或病理状态下发生的一种自发的,程序性死亡过程,作为一种机体广泛存在的生物学行为,参与了发育、内环境稳态、应激和肿瘤等众多生理和病理学过程。凋亡信号通路通常分为胞外配体途径和胞内应激信号途径。胞外配体如Fas、TNFα和TRAIL等,结合胞膜上的相应受体,使得受体胞内段募集接头蛋白(FADD和TRADD等)和凋亡起始者的Caspase-8,-10,这些分子组成了死亡诱导信号复合体(DISC),进一步活化下游的凋亡效应者Caspase-3, -6, -7,继而引发细胞凋亡。胞内应激信号,如生长因子的撤除、DNA损伤、氧化应激和癌基因的激活等,可导致线粒体外膜的泄露,细胞色素C的释放并引发凋亡小体的产生,其组成包括细胞色素C、Apaf-1和Caspase-9。作为凋亡起始者Caspase-9的激活,可进一步活化下游的凋亡效应者Caspase-3, -6, -7,继而引发细胞凋亡。因其信号通路众多,且相互影响,细胞内对凋亡的调控就更加复杂。
近年来,由RNA结合蛋白和miRNA介导的转录后调控越来越受到人们的重视,已有报道称细胞凋亡过程中该调节方式扮演重要作用。我们课题组一直关注的QKI就是一类RNA结合蛋白,属于STAR(signal transduction and activation of RNA)家族,在进化过程中高度保守,在神经系统发育过程中参与髓鞘发育。除了在神经系统中对于髓鞘的形成发挥重要功能以外,QKI蛋白在血管发生、细胞凋亡、细胞黏附、细胞生长及形态形成和器官发生等方面具有举足轻重的功能。由于转录产物的不同剪接,QKI有3种亚型,分别为QKI-5/6/7,差别主要集中在它们C末端和3’非翻译区的不同。其中QKI-5包含了一段核定位信号肽,因此主要定位于胞核中,但也可在胞核与胞浆中穿梭;而QKI-6和QKI-7则定位于胞浆中。这一差别决定了各自的亚细胞定位和功能有所不同。根据QKI与RNA结合的序列特异性,对整个mRNA进行筛选发现:QKI可能调控的下游靶基因中有众多如Bid、FOXO1、Sirt1等参与凋亡调节过程的重要基因,高度提示QKI可能在细胞凋亡中发挥作用。
本研究通过Real time PCR、Western Blotting和启动子双荧光素酶报告系统实验观察了化疗药物诱导的肿瘤细胞凋亡模型中QKI的表达变化,并通过PARP检测、Annexin V-FITC/PI流式细胞术和ROS检测等实验研究了QKI表达变化对凋亡的影响,最后探讨了QKI表达变化对化疗药物诱导的肿瘤细胞凋亡影响的相关机制。
本研究的初步结论如下:
1.构建并改造了QKI的显性负突变体,这一突变体包含二聚体形成序列但没有RNA结合功能。同时我们利用QKI异构体细胞定位的不同,在显性负突变体C端融合表达了QKI-5的核定位信号,通过与QKI-5的共定位实现了针对QKI-5亚型的特异性功能抑制。
2.利用ViraPower?腺病毒表达系统成功构建了可表达QKI-6的重组腺病毒表达载体,并包装出高滴度的重组腺病毒。
3.观察到在3种不同的化疗药物诱导的Hela细胞凋亡模型中,随着凋亡的增加QKI的mRNA和蛋白表达水平都逐渐降低,通过QKI启动子的双荧光素酶报告系统实验、QKI mRNA稳定性实验和蛋白酶体抑制实验证明,QKI表达的下调主要发生在转录和转录后水平;
4.在细胞水平过表达QKI-5蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例明显减少;相反,在细胞水平过表达QKI-7蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例明显增多;同时,在细胞水平过表达QKI-6蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例无明显变化。在主要表达QKI-5的Hela细胞中降低QKI所有异构体表达,可观察到表柔比星和顺铂诱导的细胞凋亡比例明显增多。
5.在正常培养状态下,过表达QKI-7后,Hela细胞ROS的产生增高约1.4倍,而在阿霉素或顺铂诱导细胞凋亡过程中,这种增高提高到了约3倍,表明QKI-7有促进ROS生成的作用,尤其是在化疗药物诱导的应激条件下,这种效应更加明显。在QKI-5抗凋亡作用机制研究中,通过生物信息学预测发现,FOXO3a 3’UTR存在QKI反应元件。Western blotting检测也观察到在顺铂刺激条件下,伴随着QKI-5表达的降低,FOXO3a的表达增高。在Hela细胞中过表达QKI-5可导致FOXO3a的表达降低,降低QKI的表达可引起FOXO3a的表达增高,这些都提示FOXO3a参与了QKI-5的凋亡调节效应。具体机制有待进一步研究。
综上所述,本课题组首次发现在化疗药物诱导的肿瘤细胞凋亡过程中QKI发挥重要的调节功能。在这个过程中,QKI-5蛋白可能通过降低FOXO3a的表达而发挥抗凋亡效应,QKI-7蛋白则通过增强ROS的生成而发挥促凋亡效应,提示QKI同源异构体表达水平的变化可能参与了肿瘤细胞耐药性的形成,有望成为新的肿瘤辅助治疗靶点。
Apoptosis, termed programmed cell death, occurs both in the physiological and pathological situation. As a biological behavior in vivo, apoptosis involves in many physiological and pathological processes, such as development, homeostasis, stress, tumor and etc. Apoptosis signal pathways include extracellular ligands pathway and intracellular stress signals pathway. When extracellular ligands such as Fas, TNFa or TRAIL bind to their receptors, the intracellular death domains of these receptors recruit adaptor proteins (such as FADD and TRADD) and initiator caspase-8 and -10, resulting in the formation of the death-inducing signaling complex (DISC). Caspase-8 and -10 are activated at the DISC, which cleave the executioner caspases, caspase-3, -6 and -7. The latter three caspases are the main proteases that degrade the cell. Intracellular stress signals, such as growth factor withdrawal, DNA damage, oxidative stress or oncogene activation, lead to permeabilization of the mitochondrial outer membrane and release of cytochrome c. The consequent release of cytochrome c leads to the formation of a complex– the apoptosome– which contains cytochrome c, Apaf-1 and initiator caspase-9. Caspase-9 is auto-activated by induced proximity in the apoptosome. Active caspase-9 cleaves and thereby activates the executioner caspases. Complicated and intercrossed signal pathways for apoptosis make the regulation of apoptosis a complex and diverse process.
Nowadays, more attention is paid to the post-transcriptional regulation mediated by RNA binding protein and miRNA. Posttranscriptional regulation is believed to play a vital role in the apoptosis. RNA binding protein QKI belongs to the evolutionarily conserved STAR family and has a critical role in the myelination of CNS development. However, the wide expression pattern of QKI in numerous tissues besides CNS implicates a fundamental role of QKI in other biological behavior, such as vascular development, cell apoptosis, cell adhesion, cell growth and organogenesis. The QKI gene produces a diverse set of proteins by alternative splicing. The three well studied isoforms (QKI-5, -6, and -7) appear to have different roles in development. They are constructed with the same 311-amino acid body but have different carboxyl tails consisting of 30, 8, and 14 amino acids, respectively. Because QKI-5 contains a nuclear location signal peptide (NLS), it mainly locates in the cell nuclus. QKI-6 and 7 mainly locate in the cell plasma. But sometimes QKI-5 translocates between cell plasma and cell nuclus. The distinction of location decides that isoforms of QKI have different function. According to the predicted 1400 candidate target mRNAs reported in Nat Stuct Mol Bio, many putative downstream targets are related with apoptosis, such as Bid、FOXO1、Sirt1, leading to the possibility of QKI in apoptosis regulation.
To this end, we observed the alteration of QKI expression level during the chemotherapy induced cancer cell apoptosis through Real time PCR, Western Blotting and Dual-luciferase reporter assay system. Then we investigated the influence of the QKI expression changes on apoptosis through PARP detection, Annexin V-FITC/PI flow cytometry and ROS detection. Finally, we elucidate a potential mechanism study on the role of QKI on the chemotherapy induced cancer cell apoptosis. The main findings of our study are as follows:
1. We constructed a QKI dominant negative mutation vector.The dominant negative mutation expresses peptide with the dimer sequence and without the RNA bingding ability. In the vector, the C terminal of the DN mutation was fused with the nuclear location signal of QKI-5, which thus has the same localization of QKI-5 isoform and specifically inhibits QKI-5 function.
2. The recombinant adenovirus of QKI-6 has been successfully constructed through ViraPower? adenovirus expression system, which has been expressed even at a very low MOI.
3. RT-PCR and Western-blot results showed that the mRNA and protein level of QKI decreased under the stimulation of three different chemotherapy drugs. The activity of QKI promoter was downregulated under the stimulation. QKI mRNA stability assay showed that QKI mRNA stability decreased under the stimulation. In addition, proteasome inhibitor could not reverse the downregulation of QKI expression under those stimuli. These results showed that the alteration of QKI expression level occurred on the transcriptional and post-transcriptional level.
4. Overexpression of QKI-5 resulted in down-regulation of epricubicin and cisplatin induced apoptosis in Hela cells, while overexpression of QKI-7 resulted in significant more obvious apoptosis. In addition, overexpression of QKI-6 had no obvious apoptosis on epricubicin and cisplatin induced apoptosis. Repression of endogenous of all the QKI isoforms resulted in up-regulation of epricubicin and cisplatin induced apoptosis in Hela cells, which maybe due to the predominant expression of QKI-5 in Hela cells.
5. Overexpression of QKI-7 resulted in 1.4 fold increase of ROS in cells even under the rest stage, and the increase was up to 3 fold during epricubicin and cisplatin induced apoptosis, suggesting QKI-7 promotes the production of ROS especially during the chemotherapy. For the role of QKI-5 in antagonizing apoptosis, we found that FOXO3a 3’UTR contained two QKI response elements by bioinformatics analysis. Western blotting showed that FOXO3a expression decreased when QKI-5 expression increased under the stimulation of ciaplatin in Hela cells. At the same time we observed that overexpression of QKI-5 resulted in the reduction of FOXO3a expression, suggesting a role of FOXO3a in QKI-5 mediated apoptosis regulation. Further study is needed to confirm the speculation.
In summary, we first defined an important role of QKI in chemotherapy induced apoptosis. QKI-5 has an anti-apoptosis function possibly through reducing the FOXO3a expression. In contrast, QKI-7 promotes the apoptosis of cells through enhancing the production of ROS during the chemotherapy drugs induced apoptosis. These results indicate that the alteration of QKI isoforms expression may be involved in the apoptosis under the stimulation of chemotherapy drugs. Aberrant QKI alteration under chemotherapy may be responsible for drug resistance, which is of great value for further examination. QKI may become a new target of tumor adjuvant chemotherapy.
近年来,由RNA结合蛋白和miRNA介导的转录后调控越来越受到人们的重视,已有报道称细胞凋亡过程中该调节方式扮演重要作用。我们课题组一直关注的QKI就是一类RNA结合蛋白,属于STAR(signal transduction and activation of RNA)家族,在进化过程中高度保守,在神经系统发育过程中参与髓鞘发育。除了在神经系统中对于髓鞘的形成发挥重要功能以外,QKI蛋白在血管发生、细胞凋亡、细胞黏附、细胞生长及形态形成和器官发生等方面具有举足轻重的功能。由于转录产物的不同剪接,QKI有3种亚型,分别为QKI-5/6/7,差别主要集中在它们C末端和3’非翻译区的不同。其中QKI-5包含了一段核定位信号肽,因此主要定位于胞核中,但也可在胞核与胞浆中穿梭;而QKI-6和QKI-7则定位于胞浆中。这一差别决定了各自的亚细胞定位和功能有所不同。根据QKI与RNA结合的序列特异性,对整个mRNA进行筛选发现:QKI可能调控的下游靶基因中有众多如Bid、FOXO1、Sirt1等参与凋亡调节过程的重要基因,高度提示QKI可能在细胞凋亡中发挥作用。
本研究通过Real time PCR、Western Blotting和启动子双荧光素酶报告系统实验观察了化疗药物诱导的肿瘤细胞凋亡模型中QKI的表达变化,并通过PARP检测、Annexin V-FITC/PI流式细胞术和ROS检测等实验研究了QKI表达变化对凋亡的影响,最后探讨了QKI表达变化对化疗药物诱导的肿瘤细胞凋亡影响的相关机制。
本研究的初步结论如下:
1.构建并改造了QKI的显性负突变体,这一突变体包含二聚体形成序列但没有RNA结合功能。同时我们利用QKI异构体细胞定位的不同,在显性负突变体C端融合表达了QKI-5的核定位信号,通过与QKI-5的共定位实现了针对QKI-5亚型的特异性功能抑制。
2.利用ViraPower?腺病毒表达系统成功构建了可表达QKI-6的重组腺病毒表达载体,并包装出高滴度的重组腺病毒。
3.观察到在3种不同的化疗药物诱导的Hela细胞凋亡模型中,随着凋亡的增加QKI的mRNA和蛋白表达水平都逐渐降低,通过QKI启动子的双荧光素酶报告系统实验、QKI mRNA稳定性实验和蛋白酶体抑制实验证明,QKI表达的下调主要发生在转录和转录后水平;
4.在细胞水平过表达QKI-5蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例明显减少;相反,在细胞水平过表达QKI-7蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例明显增多;同时,在细胞水平过表达QKI-6蛋白后,表柔比星和顺铂诱导的Hela细胞凋亡比例无明显变化。在主要表达QKI-5的Hela细胞中降低QKI所有异构体表达,可观察到表柔比星和顺铂诱导的细胞凋亡比例明显增多。
5.在正常培养状态下,过表达QKI-7后,Hela细胞ROS的产生增高约1.4倍,而在阿霉素或顺铂诱导细胞凋亡过程中,这种增高提高到了约3倍,表明QKI-7有促进ROS生成的作用,尤其是在化疗药物诱导的应激条件下,这种效应更加明显。在QKI-5抗凋亡作用机制研究中,通过生物信息学预测发现,FOXO3a 3’UTR存在QKI反应元件。Western blotting检测也观察到在顺铂刺激条件下,伴随着QKI-5表达的降低,FOXO3a的表达增高。在Hela细胞中过表达QKI-5可导致FOXO3a的表达降低,降低QKI的表达可引起FOXO3a的表达增高,这些都提示FOXO3a参与了QKI-5的凋亡调节效应。具体机制有待进一步研究。
综上所述,本课题组首次发现在化疗药物诱导的肿瘤细胞凋亡过程中QKI发挥重要的调节功能。在这个过程中,QKI-5蛋白可能通过降低FOXO3a的表达而发挥抗凋亡效应,QKI-7蛋白则通过增强ROS的生成而发挥促凋亡效应,提示QKI同源异构体表达水平的变化可能参与了肿瘤细胞耐药性的形成,有望成为新的肿瘤辅助治疗靶点。
Apoptosis, termed programmed cell death, occurs both in the physiological and pathological situation. As a biological behavior in vivo, apoptosis involves in many physiological and pathological processes, such as development, homeostasis, stress, tumor and etc. Apoptosis signal pathways include extracellular ligands pathway and intracellular stress signals pathway. When extracellular ligands such as Fas, TNFa or TRAIL bind to their receptors, the intracellular death domains of these receptors recruit adaptor proteins (such as FADD and TRADD) and initiator caspase-8 and -10, resulting in the formation of the death-inducing signaling complex (DISC). Caspase-8 and -10 are activated at the DISC, which cleave the executioner caspases, caspase-3, -6 and -7. The latter three caspases are the main proteases that degrade the cell. Intracellular stress signals, such as growth factor withdrawal, DNA damage, oxidative stress or oncogene activation, lead to permeabilization of the mitochondrial outer membrane and release of cytochrome c. The consequent release of cytochrome c leads to the formation of a complex– the apoptosome– which contains cytochrome c, Apaf-1 and initiator caspase-9. Caspase-9 is auto-activated by induced proximity in the apoptosome. Active caspase-9 cleaves and thereby activates the executioner caspases. Complicated and intercrossed signal pathways for apoptosis make the regulation of apoptosis a complex and diverse process.
Nowadays, more attention is paid to the post-transcriptional regulation mediated by RNA binding protein and miRNA. Posttranscriptional regulation is believed to play a vital role in the apoptosis. RNA binding protein QKI belongs to the evolutionarily conserved STAR family and has a critical role in the myelination of CNS development. However, the wide expression pattern of QKI in numerous tissues besides CNS implicates a fundamental role of QKI in other biological behavior, such as vascular development, cell apoptosis, cell adhesion, cell growth and organogenesis. The QKI gene produces a diverse set of proteins by alternative splicing. The three well studied isoforms (QKI-5, -6, and -7) appear to have different roles in development. They are constructed with the same 311-amino acid body but have different carboxyl tails consisting of 30, 8, and 14 amino acids, respectively. Because QKI-5 contains a nuclear location signal peptide (NLS), it mainly locates in the cell nuclus. QKI-6 and 7 mainly locate in the cell plasma. But sometimes QKI-5 translocates between cell plasma and cell nuclus. The distinction of location decides that isoforms of QKI have different function. According to the predicted 1400 candidate target mRNAs reported in Nat Stuct Mol Bio, many putative downstream targets are related with apoptosis, such as Bid、FOXO1、Sirt1, leading to the possibility of QKI in apoptosis regulation.
To this end, we observed the alteration of QKI expression level during the chemotherapy induced cancer cell apoptosis through Real time PCR, Western Blotting and Dual-luciferase reporter assay system. Then we investigated the influence of the QKI expression changes on apoptosis through PARP detection, Annexin V-FITC/PI flow cytometry and ROS detection. Finally, we elucidate a potential mechanism study on the role of QKI on the chemotherapy induced cancer cell apoptosis. The main findings of our study are as follows:
1. We constructed a QKI dominant negative mutation vector.The dominant negative mutation expresses peptide with the dimer sequence and without the RNA bingding ability. In the vector, the C terminal of the DN mutation was fused with the nuclear location signal of QKI-5, which thus has the same localization of QKI-5 isoform and specifically inhibits QKI-5 function.
2. The recombinant adenovirus of QKI-6 has been successfully constructed through ViraPower? adenovirus expression system, which has been expressed even at a very low MOI.
3. RT-PCR and Western-blot results showed that the mRNA and protein level of QKI decreased under the stimulation of three different chemotherapy drugs. The activity of QKI promoter was downregulated under the stimulation. QKI mRNA stability assay showed that QKI mRNA stability decreased under the stimulation. In addition, proteasome inhibitor could not reverse the downregulation of QKI expression under those stimuli. These results showed that the alteration of QKI expression level occurred on the transcriptional and post-transcriptional level.
4. Overexpression of QKI-5 resulted in down-regulation of epricubicin and cisplatin induced apoptosis in Hela cells, while overexpression of QKI-7 resulted in significant more obvious apoptosis. In addition, overexpression of QKI-6 had no obvious apoptosis on epricubicin and cisplatin induced apoptosis. Repression of endogenous of all the QKI isoforms resulted in up-regulation of epricubicin and cisplatin induced apoptosis in Hela cells, which maybe due to the predominant expression of QKI-5 in Hela cells.
5. Overexpression of QKI-7 resulted in 1.4 fold increase of ROS in cells even under the rest stage, and the increase was up to 3 fold during epricubicin and cisplatin induced apoptosis, suggesting QKI-7 promotes the production of ROS especially during the chemotherapy. For the role of QKI-5 in antagonizing apoptosis, we found that FOXO3a 3’UTR contained two QKI response elements by bioinformatics analysis. Western blotting showed that FOXO3a expression decreased when QKI-5 expression increased under the stimulation of ciaplatin in Hela cells. At the same time we observed that overexpression of QKI-5 resulted in the reduction of FOXO3a expression, suggesting a role of FOXO3a in QKI-5 mediated apoptosis regulation. Further study is needed to confirm the speculation.
In summary, we first defined an important role of QKI in chemotherapy induced apoptosis. QKI-5 has an anti-apoptosis function possibly through reducing the FOXO3a expression. In contrast, QKI-7 promotes the apoptosis of cells through enhancing the production of ROS during the chemotherapy drugs induced apoptosis. These results indicate that the alteration of QKI isoforms expression may be involved in the apoptosis under the stimulation of chemotherapy drugs. Aberrant QKI alteration under chemotherapy may be responsible for drug resistance, which is of great value for further examination. QKI may become a new target of tumor adjuvant chemotherapy.
引文
1. Thomas G. Cotter. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009;9(7):501-507.
2. Glucksmann A. Cell deaths in normal vertebrate ontogeny. Biol Rev. 1951;26: 59–83.
3. Lockshin, R. A. & Williams, C. M. Programmed cell death-1. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J. Insect Physiol. 1965;11:123–133.
4. Kerr, J. F. A histochemical study of hypertrophy and ishaemic injury or rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 1965;90: 419–435.
5. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer. 1972;26:239–57.
6. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284:555–6.
7.李玉林,文继舫,唐建武.病理学.第7版.北京:人民卫生出版社, 2008.
17-18.
8.查锡良,药立波.医学分子生物学.北京:人民卫生出版社, 2004. 513-537.
9. John C. Reed. Apoptosis-targeted therapies for cancer. Cancer Cell. 2003;3:17-22.
10. Green DR. Apoptotic pathways: paper wraps stone blunts scissors. Cell. 2000;102(1):1-4.
11. Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol.1999;17:331–367.
12. Green, D.R., and Reed, J.C. Mitochondria and apoptosis. Science. 1998;281: 1309–1312.
13. Kroemer, G., and Reed, J.C. Mitochondrial control of cell death. Nat. Med. 2000;6:513–519.
14. Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol. 2000;150:887–894.
15. B.Motyka, G.Korbutt, M.Pinkoski, J.Heibein, A.Caputo, M.Hobman, M.Barry, I.Shostak, T.Sawchuk, C.Holmes. Manose 6/phosphate/ insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell. 2000;103:491-500.
16. Dennis Keefe, Lianfa Shi, Stefan Feske, Ramiro Massol, FranciscoNavarro, Tomas Kirchhausen, Judy Lieberman. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity. 2005;23:249-262.
17. Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, Chávez R, Lascurain R. Cell death mechanism induced by cytotoxic lymphocytes.Cellular&Molecular Immunology. 2009;6(1):15-25.
18. Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9:402–12.
19. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by transactivation-deficient p53. Genes Dev. 1995;9:2170–83.
20. Douglas R. Green and Guido Kroemer. Cytoplasmic Functions of the Tumor Suppressor p53. Nature. 2009;458(7242):1127.
21. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. The Journal of Cell Biology. 1994;124 (4):619–26.
22. Aoudjit F, Vuori K. Matrix attachment regulates Fasinduced apoptosis in endothelial cells: a role for c-flip and implications for anoikis. J Cell Biol 2001;152:633–43.
23. Rytomaa M, Martins LM, Downward J. Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr Biol. 1999;9:1043–6.
24. Paola Chiarugi, Elisa Giannoni. Anoikis: A necessary death program for anchorage-dependent cells. Biochemical pharmacology. 2008;76:1352-1364.
25. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
26. I Petak, R P Danam, D M Tillman, R Vernes, S R Howell, L Berczi, L Kopper, T P Brent, J A Houghton. Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma. Cell Death and Differentiation. 2003;10(2):211–217.
27. Inna Lavrik, Alexander Golks, Peter H. Krammer. Death receptor Signaling Journal of Cell Science. 2005;118:265-267.
28. Pitti R M, Marsters S A, Lawrence D A, Roy M, Kischkel F C, Dowd P, Huang A, Donahue C J, Sherwood S W, Baldwin D T, Godowski P J, Wood W I, Gurney A L, Hillan K J, Cohen R L, Goddard A D, Botstein D, Ashkenazi A. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998;396(6712):699–703.
29. Wilfried Roth, Stefan Isenmann, Mitsutoshi Nakamura, Michael Platten, Wolfgang Wick, Paul Kleihues, Mathias B?hr, Hiroko Ohgaki, Avi Ashkenazi and Michael Weller. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Research. 2001;61(6):2759–2765.
30. Sheikh MS, Huang Y, Fernandez-Salas EA, El-Deiry WS, Friess H, Amundson S, Yin J, Meltzer SJ, Holbrook NJ, Fornace AJ Jr. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53- regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene. 1999 ;18(28):4153–4159.
31. B. C. Barnhart, J. C. Lee, E. C. Alappat, M. E. Peter. The death effector domain protein family. Oncogene. 2003;22(53):8634–864.
32. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.
33. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 1997;91:627–37.
34. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005;17:525–35.
35. Simone Fulda. Evasion of Apoptosis as a Cellular Stress Response in Cancer. International Journal of Cell Biology. 2010;2010:370835.
36. S. M. Lewis and M. Holcik. IRES in distress: translational regulation of the inhibitor of apoptosis proteins XIAP and HIAP2 during cell stress. Cell Death and Differentiation. 2005;12(6):547–553.
37. Gilman, A. The initial clinical trial of nitrogen mustard. Am. J. Surg. 1963;105:574–578.
38. Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F. & Wolff, J. A. Temporary remissions in acute leukemia in children produced by folic antagonist, 4-aminopteroylglutamic acid (aminopterin). N. Engl. J. Med. 1948;238:787–793.
39. Li, M. C., Hertz, R. & Bergenstal, D. M. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N. Engl. J. Med. 1958;259:66–74.
40. Jaffe, N., Frei, E. 3rd, Traggis, D. & Bishop, Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N. Engl. J. Med. 1974;291:994–997.
41. Frei, E. 3rd et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965;26:642–656.
42. Kelland, L. R. Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur. J. Cancer. 2004;40:827–836.
43. Rubinstein L, Plowman J, Boyd MR. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J. Natl Cancer Inst. 1989;81:1088–1092.
44. Cheson, B.D. and Rummel, M.J. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27:1492-501.
45. Bauer GB, Povirk LF. Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence. Nucleic Acids Res. 1997;25:1211-1218.
46. Dong Wang and Stephen J. Lippard. Cellular Processing Of Platinum Anticancer Drugs. Nat Rev Drug Discov. 2005;4(4):307-20.
47. Pruefer FG, Lizarraga F, Maldonado V, Melendez-Zajgla J. Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells. J Chemother. 2008;20(3):348–54.
48. Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP. Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol. Ther. 2000;87(2-3): 227–53.
49. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur. J. Clin. Pharmacol. 2008;64(8):753–67.
50. Wyatt MD, Wilson DM 3rd. Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci. 2009;66(5):788-99.
51. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65(3):168-73.
52. Edward Chu , Vincent DeVita Jr. Physicians' Cancer Chemotherapy Drug Manual. 2009:371-374.
53. Gadducci A, Cosio S, Muraca S, Genazzani AR. Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications. Eur J Gynaecol Oncol. 2002;23(5):390-6.
54. M.E. Wall, M.C.Wani, C.E. Cook, K.H.Palmer, A.I.McPhail, G.A.Sim. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate. J. Am. Chem. Soc. 1966;88:3888–3890.
55. Boulares AH, Zoltoski AJ, Contreras FJ, Yakovlev AG, Yoshihara K, Smulson ME. Regulation of DNAS1L3 endonuclease activity by poly(ADP-ribosyl)ation during etoposide-induced apoptosis. Role of poly(ADP-ribose) polymerase-1 cleavage in endonuclease activation. J Biol Chem. 2002;277(1):372-8.
56. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference bydoxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994; 45(4):649–56.
57. Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976;36(8):2891–5.
58. Lim YB, Park TJ, Lim IK. B cell tranlocation gene 2 enhances susceptibility of Hela cells to doxorubicin-induced oxidative damage. J Biol Chem. 2008;283(48):33110-8.
59. Esnault S, Malter JS: Hyaluronic acid or TNF-alpha plus fibronectin triggers granulocyte macrophage-colony-stimulating factor mRNA stabilization in eosinophils yet engages differential intracellular pathways and mRNA binding proteins. J Immunol 2003, 171(12):6780-6787.
60. Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J. The 3' untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 2001, 21(3):721-730.
61. Ming XF, Stoecklin G, Lu M, Looser R, Moroni C. Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase. Mol Cell Biol 2001, 21(17):5778-5789.
62. Vernet C, Artzt K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet 1997, 13(12):479-484.
63. Chenard CA, Richard S. New implications for the QUAKING RNA binding protein in human disease. J Neurosci Res 2008, 86(2):233-242.
64. McInnes LA, Lauriat TL. RNA metabolism and dysmyelination in schizophrenia. Neurosci Biobehav Rev 2006, 30(4):551-561.
65. Larocque D, Galarneau A, Liu HN, Scott M, Almazan G, Richard S. Protection of p27(Kip1) mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation. Nat Neurosci 2005, 8(1):27-33.
66. Ebersole TA, Chen Q, Justice MJ, Artzt K. The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins. Nat Genet 1996, 12(3):260-265.
67. Hardy RJ, Loushin CL, Friedrich VL, Jr., Chen Q, Ebersole TA, Lazzarini RA, Artzt K. Neural cell type-specific expression of QKI proteins is altered in quakingviable mutant mice. J Neurosci 1996, 16(24):7941-7949.
68. Wu J, Zhou L, Tonissen K, Tee R, Artzt K. The quaking I-5 protein (QKI-5) has a novel nuclear localization signal and shuttles between the nucleus and the cytoplasm. J Biol Chem 1999, 274(41):29202-29210.
69. Larocque D, Pilotte J, Chen T, Cloutier F, Massie B, Pedraza L, Couture R, Lasko P, Almazan G, Richard S. Nuclear retention of MBP mRNAs in thequaking viable mice. Neuron 2002, 36(5):815-829.
70. Pilotte J, Larocque D, Richard S. Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer. Genes Dev 2001, 15(7):845-858.
71. Noveroske JK, Lai L, Gaussin V, Northrop JL, Nakamura H, Hirschi KK, Justice MJ. Quaking is essential for blood vessel development. Genesis 2002, 32(3):218-230.
72. Bockbrader K, Feng Y. Essential function, sophisticated regulation and pathological impact of the selective RNA-binding protein QKI in CNS myelin development. Future Neurol 2008, 3(6):655-668.
73. Galarneau A, Richard S. Target RNA motif and target mRNAs of the Quaking STAR protein. Nat Struct Mol Biol 2005, 12(8):691-698.
74. Ryder SP, Frater LA, Abramovitz DL, Goodwin EB, Williamson JR. RNA target specificity of the STAR/GSG domain post-transcriptional regulatory protein GLD-1. Nat Struct Mol Biol 2004, 11(1):20-28.
75. Dawson MR, Polito A, Levine JM, Reynolds R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 2003, 24(2):476-488.
76. Hardy RJ. Molecular defects in the dysmyelinating mutant quaking. J Neurosci Res 1998, 51(4):417-422.
77. Bj?rn Schumacher, Momoyo Hanazawa, Min-Ho Lee, Sudhir Nayak, Katrin Volkmann. Translational Repression of C. elegans p53 by GLD-1 Regulates DNA Damage-Induced Apoptosis. Cell. 2005;120:357–368.
78. Zhang Y, Lu Z, Ku L, Chen Y, Wang H, Feng Y. Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism. Embo J 2003, 22(8):1801-1810.
79. Aberg K, Saetre P, Jareborg N, Jazin E. Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci U S A 2006, 103(19):7482-7487.
80. Aberg K, Saetre P, Lindholm E, Ekholm B, Pettersson U, Adolfsson R, Jazin E. Human QKI, a new candidate gene for schizophrenia involved in myelination. Am J Med Genet B Neuropsychiatr Genet 2006, 141B(1):84-90.
81. Haroutunian V, Katsel P, Dracheva S, Davis KL. The human homolog of the QKI gene affected in the severe dysmyelination "quaking" mouse phenotype: downregulated in multiple brain regions in schizophrenia. Am J Psychiatry 2006, 163(10):1834-1837.
82. Lauriat TL, Shiue L, Haroutunian V, Verbitsky M, Ares M, Jr., Ospina L, McInnes LA. Developmental expression profile of quaking, a candidate gene forschizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity. J Neurosci Res 2008, 86(4):785-796.
83. Kondo T, Furuta T, Mitsunaga K, Ebersole TA, Shichiri M, Wu J, Artzt K, Yamamura K, Abe K. Genomic organization and expression analysis of the mouse qkI locus. Mamm Genome 1999, 10(7):662-669.
84. Lorenzetti D, Antalffy B, Vogel H, Noveroske J, Armstrong D, Justice M. The neurological mutant quaking(viable) is Parkin deficient. Mamm Genome 2004, 15(3):210-217.
85. Cox RD, Hugill A, Shedlovsky A, Noveroske JK, Best S, Justice MJ, Lehrach H, Dove WF. Contrasting effects of ENU induced embryonic lethal mutations of the quaking gene. Genomics 1999, 57(3):333-341.
86. Zhao L, Tian D, Xia M, Macklin WB, Feng Y. Rescuing qkV dysmyelination by a single isoform of the selective RNA-binding protein QKI. J Neurosci 2006, 26(44):11278-11286.
87. Casaccia-Bonnefil P, Hardy RJ, Teng KK, Levine JM, Koff A, Chao MV. Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation. Development 1999, 126(18):4027-4037.
88. Wegner M, Stolt CC. From stem cells to neurons and glia: a Soxist's view of neural development. Trends Neurosci 2005, 28(11):583-588.
89. Vouyiouklis DA, Brophy PJ. Microtubule-associated protein MAP1B expression precedes the morphological differentiation of oligodendrocytes. J Neurosci Res 1993, 35(3):257-267.
90. Fischer I, Konola J, Cochary E. Microtubule associated protein (MAP1B) is present in cultured oligodendrocytes and co-localizes with tubulin. J Neurosci Res 1990, 27(1):112-124.
91. Wu HY, Dawson MR, Reynolds R, Hardy RJ. Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain. Mol Cell Neurosci 2001, 17(2):292-302.
92. Lu Z, Ku L, Chen Y, Feng Y. Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in posttranscriptional regulation. J Biol Chem 2005, 280(1):389-395.
93. Wei Q, Miskimins WK, Miskimins R. The Sp1 family of transcription factors is involved in p27(Kip1)-mediated activation of myelin basic protein gene expression. Mol Cell Biol 2003, 23(12):4035-4045.
94. Marquardt T, Pfaff SL. Cracking the transcriptional code for cell specification in the neural tube. Cell 2001, 106(6):651-654.
95. Gokhan S, Marin-Husstege M, Yung SY, Fontanez D, Casaccia-Bonnefil P,Mehler MF. Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J Neurosci 2005, 25(36):8311-8321.
96. Kubicki M, McCarley RW, Shenton ME. Evidence for white matter abnormalities in schizophrenia. Curr Opin Psychiatry 2005, 18(2):121-134.
97. Havlioglu N, Wang J, Fushimi K, Vibranovski MD, Kan Z, Gish W, Fedorov A, Long M, Wu JY. An intronic signal for alternative splicing in the human genome. PLoS One 2007, 2(11):e1246.
98. Wang E, Dimova N, Cambi F. PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes. Nucleic Acids Res 2007, 35(12):4164-4178.
99. Garneau NL, Wilusz J, Wilusz CJ. The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 2007, 8(2):113-126.
100. Guhaniyogi J, Brewer G. Regulation of mRNA stability in mammalian cells. Gene 2001, 265(1-2):11-23.
101. Guodong Yang, Haiyan Fu, Jie Zhang, Xiaozhao Lu, Fang Yu, Liang Jin, Liyuan Bai, Bo Huang, Lan Shen, Yue Feng, Libo Yao, Zifan Lu. RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer. Gastroenterology. 2010;138(1):231-40.
102. Tatsuya Kondo,Tokiko Furuta,Kanae Mitsunaga,Thomas A. Ebersole,Motoaki Shichiri,Jiang Wu, Karen Artzt, Ken-ichi Yamamura, Kuniya Abe. Genomic organization and expression analysis of the mouse qkI locus. Mammalian Genome. 1999;10:662–669.
103. Haojie Huang and Donald J. Tindall. Dynamic FoxO transcription factors. Journal of Cell Science.120; 2479-2487.
104. Rosaline C-Y. Hui, Richard E. Francis, Stephanie K. Guest, Joana R. Costa, Ana R. Gomes, Stephen S. Myatt, Jan J. Brosens, Eric W-F. Lam. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther. 2008;7:670–8.
105. Fernández de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther. 2008;7(10):3237-46.
2. Glucksmann A. Cell deaths in normal vertebrate ontogeny. Biol Rev. 1951;26: 59–83.
3. Lockshin, R. A. & Williams, C. M. Programmed cell death-1. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J. Insect Physiol. 1965;11:123–133.
4. Kerr, J. F. A histochemical study of hypertrophy and ishaemic injury or rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 1965;90: 419–435.
5. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer. 1972;26:239–57.
6. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284:555–6.
7.李玉林,文继舫,唐建武.病理学.第7版.北京:人民卫生出版社, 2008.
17-18.
8.查锡良,药立波.医学分子生物学.北京:人民卫生出版社, 2004. 513-537.
9. John C. Reed. Apoptosis-targeted therapies for cancer. Cancer Cell. 2003;3:17-22.
10. Green DR. Apoptotic pathways: paper wraps stone blunts scissors. Cell. 2000;102(1):1-4.
11. Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol.1999;17:331–367.
12. Green, D.R., and Reed, J.C. Mitochondria and apoptosis. Science. 1998;281: 1309–1312.
13. Kroemer, G., and Reed, J.C. Mitochondrial control of cell death. Nat. Med. 2000;6:513–519.
14. Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol. 2000;150:887–894.
15. B.Motyka, G.Korbutt, M.Pinkoski, J.Heibein, A.Caputo, M.Hobman, M.Barry, I.Shostak, T.Sawchuk, C.Holmes. Manose 6/phosphate/ insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell. 2000;103:491-500.
16. Dennis Keefe, Lianfa Shi, Stefan Feske, Ramiro Massol, FranciscoNavarro, Tomas Kirchhausen, Judy Lieberman. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity. 2005;23:249-262.
17. Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, Chávez R, Lascurain R. Cell death mechanism induced by cytotoxic lymphocytes.Cellular&Molecular Immunology. 2009;6(1):15-25.
18. Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9:402–12.
19. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by transactivation-deficient p53. Genes Dev. 1995;9:2170–83.
20. Douglas R. Green and Guido Kroemer. Cytoplasmic Functions of the Tumor Suppressor p53. Nature. 2009;458(7242):1127.
21. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. The Journal of Cell Biology. 1994;124 (4):619–26.
22. Aoudjit F, Vuori K. Matrix attachment regulates Fasinduced apoptosis in endothelial cells: a role for c-flip and implications for anoikis. J Cell Biol 2001;152:633–43.
23. Rytomaa M, Martins LM, Downward J. Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr Biol. 1999;9:1043–6.
24. Paola Chiarugi, Elisa Giannoni. Anoikis: A necessary death program for anchorage-dependent cells. Biochemical pharmacology. 2008;76:1352-1364.
25. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
26. I Petak, R P Danam, D M Tillman, R Vernes, S R Howell, L Berczi, L Kopper, T P Brent, J A Houghton. Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma. Cell Death and Differentiation. 2003;10(2):211–217.
27. Inna Lavrik, Alexander Golks, Peter H. Krammer. Death receptor Signaling Journal of Cell Science. 2005;118:265-267.
28. Pitti R M, Marsters S A, Lawrence D A, Roy M, Kischkel F C, Dowd P, Huang A, Donahue C J, Sherwood S W, Baldwin D T, Godowski P J, Wood W I, Gurney A L, Hillan K J, Cohen R L, Goddard A D, Botstein D, Ashkenazi A. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998;396(6712):699–703.
29. Wilfried Roth, Stefan Isenmann, Mitsutoshi Nakamura, Michael Platten, Wolfgang Wick, Paul Kleihues, Mathias B?hr, Hiroko Ohgaki, Avi Ashkenazi and Michael Weller. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Research. 2001;61(6):2759–2765.
30. Sheikh MS, Huang Y, Fernandez-Salas EA, El-Deiry WS, Friess H, Amundson S, Yin J, Meltzer SJ, Holbrook NJ, Fornace AJ Jr. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53- regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene. 1999 ;18(28):4153–4159.
31. B. C. Barnhart, J. C. Lee, E. C. Alappat, M. E. Peter. The death effector domain protein family. Oncogene. 2003;22(53):8634–864.
32. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.
33. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 1997;91:627–37.
34. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005;17:525–35.
35. Simone Fulda. Evasion of Apoptosis as a Cellular Stress Response in Cancer. International Journal of Cell Biology. 2010;2010:370835.
36. S. M. Lewis and M. Holcik. IRES in distress: translational regulation of the inhibitor of apoptosis proteins XIAP and HIAP2 during cell stress. Cell Death and Differentiation. 2005;12(6):547–553.
37. Gilman, A. The initial clinical trial of nitrogen mustard. Am. J. Surg. 1963;105:574–578.
38. Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F. & Wolff, J. A. Temporary remissions in acute leukemia in children produced by folic antagonist, 4-aminopteroylglutamic acid (aminopterin). N. Engl. J. Med. 1948;238:787–793.
39. Li, M. C., Hertz, R. & Bergenstal, D. M. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N. Engl. J. Med. 1958;259:66–74.
40. Jaffe, N., Frei, E. 3rd, Traggis, D. & Bishop, Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N. Engl. J. Med. 1974;291:994–997.
41. Frei, E. 3rd et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965;26:642–656.
42. Kelland, L. R. Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur. J. Cancer. 2004;40:827–836.
43. Rubinstein L, Plowman J, Boyd MR. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J. Natl Cancer Inst. 1989;81:1088–1092.
44. Cheson, B.D. and Rummel, M.J. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27:1492-501.
45. Bauer GB, Povirk LF. Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence. Nucleic Acids Res. 1997;25:1211-1218.
46. Dong Wang and Stephen J. Lippard. Cellular Processing Of Platinum Anticancer Drugs. Nat Rev Drug Discov. 2005;4(4):307-20.
47. Pruefer FG, Lizarraga F, Maldonado V, Melendez-Zajgla J. Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells. J Chemother. 2008;20(3):348–54.
48. Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP. Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol. Ther. 2000;87(2-3): 227–53.
49. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur. J. Clin. Pharmacol. 2008;64(8):753–67.
50. Wyatt MD, Wilson DM 3rd. Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci. 2009;66(5):788-99.
51. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65(3):168-73.
52. Edward Chu , Vincent DeVita Jr. Physicians' Cancer Chemotherapy Drug Manual. 2009:371-374.
53. Gadducci A, Cosio S, Muraca S, Genazzani AR. Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications. Eur J Gynaecol Oncol. 2002;23(5):390-6.
54. M.E. Wall, M.C.Wani, C.E. Cook, K.H.Palmer, A.I.McPhail, G.A.Sim. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate. J. Am. Chem. Soc. 1966;88:3888–3890.
55. Boulares AH, Zoltoski AJ, Contreras FJ, Yakovlev AG, Yoshihara K, Smulson ME. Regulation of DNAS1L3 endonuclease activity by poly(ADP-ribosyl)ation during etoposide-induced apoptosis. Role of poly(ADP-ribose) polymerase-1 cleavage in endonuclease activation. J Biol Chem. 2002;277(1):372-8.
56. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference bydoxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994; 45(4):649–56.
57. Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976;36(8):2891–5.
58. Lim YB, Park TJ, Lim IK. B cell tranlocation gene 2 enhances susceptibility of Hela cells to doxorubicin-induced oxidative damage. J Biol Chem. 2008;283(48):33110-8.
59. Esnault S, Malter JS: Hyaluronic acid or TNF-alpha plus fibronectin triggers granulocyte macrophage-colony-stimulating factor mRNA stabilization in eosinophils yet engages differential intracellular pathways and mRNA binding proteins. J Immunol 2003, 171(12):6780-6787.
60. Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J. The 3' untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 2001, 21(3):721-730.
61. Ming XF, Stoecklin G, Lu M, Looser R, Moroni C. Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase. Mol Cell Biol 2001, 21(17):5778-5789.
62. Vernet C, Artzt K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet 1997, 13(12):479-484.
63. Chenard CA, Richard S. New implications for the QUAKING RNA binding protein in human disease. J Neurosci Res 2008, 86(2):233-242.
64. McInnes LA, Lauriat TL. RNA metabolism and dysmyelination in schizophrenia. Neurosci Biobehav Rev 2006, 30(4):551-561.
65. Larocque D, Galarneau A, Liu HN, Scott M, Almazan G, Richard S. Protection of p27(Kip1) mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation. Nat Neurosci 2005, 8(1):27-33.
66. Ebersole TA, Chen Q, Justice MJ, Artzt K. The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins. Nat Genet 1996, 12(3):260-265.
67. Hardy RJ, Loushin CL, Friedrich VL, Jr., Chen Q, Ebersole TA, Lazzarini RA, Artzt K. Neural cell type-specific expression of QKI proteins is altered in quakingviable mutant mice. J Neurosci 1996, 16(24):7941-7949.
68. Wu J, Zhou L, Tonissen K, Tee R, Artzt K. The quaking I-5 protein (QKI-5) has a novel nuclear localization signal and shuttles between the nucleus and the cytoplasm. J Biol Chem 1999, 274(41):29202-29210.
69. Larocque D, Pilotte J, Chen T, Cloutier F, Massie B, Pedraza L, Couture R, Lasko P, Almazan G, Richard S. Nuclear retention of MBP mRNAs in thequaking viable mice. Neuron 2002, 36(5):815-829.
70. Pilotte J, Larocque D, Richard S. Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer. Genes Dev 2001, 15(7):845-858.
71. Noveroske JK, Lai L, Gaussin V, Northrop JL, Nakamura H, Hirschi KK, Justice MJ. Quaking is essential for blood vessel development. Genesis 2002, 32(3):218-230.
72. Bockbrader K, Feng Y. Essential function, sophisticated regulation and pathological impact of the selective RNA-binding protein QKI in CNS myelin development. Future Neurol 2008, 3(6):655-668.
73. Galarneau A, Richard S. Target RNA motif and target mRNAs of the Quaking STAR protein. Nat Struct Mol Biol 2005, 12(8):691-698.
74. Ryder SP, Frater LA, Abramovitz DL, Goodwin EB, Williamson JR. RNA target specificity of the STAR/GSG domain post-transcriptional regulatory protein GLD-1. Nat Struct Mol Biol 2004, 11(1):20-28.
75. Dawson MR, Polito A, Levine JM, Reynolds R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 2003, 24(2):476-488.
76. Hardy RJ. Molecular defects in the dysmyelinating mutant quaking. J Neurosci Res 1998, 51(4):417-422.
77. Bj?rn Schumacher, Momoyo Hanazawa, Min-Ho Lee, Sudhir Nayak, Katrin Volkmann. Translational Repression of C. elegans p53 by GLD-1 Regulates DNA Damage-Induced Apoptosis. Cell. 2005;120:357–368.
78. Zhang Y, Lu Z, Ku L, Chen Y, Wang H, Feng Y. Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism. Embo J 2003, 22(8):1801-1810.
79. Aberg K, Saetre P, Jareborg N, Jazin E. Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci U S A 2006, 103(19):7482-7487.
80. Aberg K, Saetre P, Lindholm E, Ekholm B, Pettersson U, Adolfsson R, Jazin E. Human QKI, a new candidate gene for schizophrenia involved in myelination. Am J Med Genet B Neuropsychiatr Genet 2006, 141B(1):84-90.
81. Haroutunian V, Katsel P, Dracheva S, Davis KL. The human homolog of the QKI gene affected in the severe dysmyelination "quaking" mouse phenotype: downregulated in multiple brain regions in schizophrenia. Am J Psychiatry 2006, 163(10):1834-1837.
82. Lauriat TL, Shiue L, Haroutunian V, Verbitsky M, Ares M, Jr., Ospina L, McInnes LA. Developmental expression profile of quaking, a candidate gene forschizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity. J Neurosci Res 2008, 86(4):785-796.
83. Kondo T, Furuta T, Mitsunaga K, Ebersole TA, Shichiri M, Wu J, Artzt K, Yamamura K, Abe K. Genomic organization and expression analysis of the mouse qkI locus. Mamm Genome 1999, 10(7):662-669.
84. Lorenzetti D, Antalffy B, Vogel H, Noveroske J, Armstrong D, Justice M. The neurological mutant quaking(viable) is Parkin deficient. Mamm Genome 2004, 15(3):210-217.
85. Cox RD, Hugill A, Shedlovsky A, Noveroske JK, Best S, Justice MJ, Lehrach H, Dove WF. Contrasting effects of ENU induced embryonic lethal mutations of the quaking gene. Genomics 1999, 57(3):333-341.
86. Zhao L, Tian D, Xia M, Macklin WB, Feng Y. Rescuing qkV dysmyelination by a single isoform of the selective RNA-binding protein QKI. J Neurosci 2006, 26(44):11278-11286.
87. Casaccia-Bonnefil P, Hardy RJ, Teng KK, Levine JM, Koff A, Chao MV. Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation. Development 1999, 126(18):4027-4037.
88. Wegner M, Stolt CC. From stem cells to neurons and glia: a Soxist's view of neural development. Trends Neurosci 2005, 28(11):583-588.
89. Vouyiouklis DA, Brophy PJ. Microtubule-associated protein MAP1B expression precedes the morphological differentiation of oligodendrocytes. J Neurosci Res 1993, 35(3):257-267.
90. Fischer I, Konola J, Cochary E. Microtubule associated protein (MAP1B) is present in cultured oligodendrocytes and co-localizes with tubulin. J Neurosci Res 1990, 27(1):112-124.
91. Wu HY, Dawson MR, Reynolds R, Hardy RJ. Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain. Mol Cell Neurosci 2001, 17(2):292-302.
92. Lu Z, Ku L, Chen Y, Feng Y. Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in posttranscriptional regulation. J Biol Chem 2005, 280(1):389-395.
93. Wei Q, Miskimins WK, Miskimins R. The Sp1 family of transcription factors is involved in p27(Kip1)-mediated activation of myelin basic protein gene expression. Mol Cell Biol 2003, 23(12):4035-4045.
94. Marquardt T, Pfaff SL. Cracking the transcriptional code for cell specification in the neural tube. Cell 2001, 106(6):651-654.
95. Gokhan S, Marin-Husstege M, Yung SY, Fontanez D, Casaccia-Bonnefil P,Mehler MF. Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J Neurosci 2005, 25(36):8311-8321.
96. Kubicki M, McCarley RW, Shenton ME. Evidence for white matter abnormalities in schizophrenia. Curr Opin Psychiatry 2005, 18(2):121-134.
97. Havlioglu N, Wang J, Fushimi K, Vibranovski MD, Kan Z, Gish W, Fedorov A, Long M, Wu JY. An intronic signal for alternative splicing in the human genome. PLoS One 2007, 2(11):e1246.
98. Wang E, Dimova N, Cambi F. PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes. Nucleic Acids Res 2007, 35(12):4164-4178.
99. Garneau NL, Wilusz J, Wilusz CJ. The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 2007, 8(2):113-126.
100. Guhaniyogi J, Brewer G. Regulation of mRNA stability in mammalian cells. Gene 2001, 265(1-2):11-23.
101. Guodong Yang, Haiyan Fu, Jie Zhang, Xiaozhao Lu, Fang Yu, Liang Jin, Liyuan Bai, Bo Huang, Lan Shen, Yue Feng, Libo Yao, Zifan Lu. RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer. Gastroenterology. 2010;138(1):231-40.
102. Tatsuya Kondo,Tokiko Furuta,Kanae Mitsunaga,Thomas A. Ebersole,Motoaki Shichiri,Jiang Wu, Karen Artzt, Ken-ichi Yamamura, Kuniya Abe. Genomic organization and expression analysis of the mouse qkI locus. Mammalian Genome. 1999;10:662–669.
103. Haojie Huang and Donald J. Tindall. Dynamic FoxO transcription factors. Journal of Cell Science.120; 2479-2487.
104. Rosaline C-Y. Hui, Richard E. Francis, Stephanie K. Guest, Joana R. Costa, Ana R. Gomes, Stephen S. Myatt, Jan J. Brosens, Eric W-F. Lam. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther. 2008;7:670–8.
105. Fernández de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther. 2008;7(10):3237-46.