EDAG相互作用蛋白THAP11 对NF-κB活性的抑制
摘要
EDAG基因是本实验室分离克隆的一种与造血细胞增殖分化密切相关的新基因。EDAG基因是从4月龄人胎肝组织与成年肝组织的差异表达基因EST库中分离到的一种新基因片段，mRNA长约2.2 kb,经筛选人胎肝 cDNA文库获1.9kb片段，命名为红系分化相关基因（erythroid differentiation-associated gene，EDAG）。序列分析推测该基因编码484 个氨基酸组成的蛋白质，且在体外实验得到证实，该蛋白定位于染色体9q22。
前期研究表明，EDAG特异表达于造血组织与胚胎组织，并在白血病细胞中高表达。利用反义核酸技术抑制EDAG表达后，可以抑制白血病细胞的增殖能力以及诱导剂所诱导的分化能力。在细胞因子依赖的细胞株中高表达EDAG 可使细胞对细胞因子的依赖性降低，并表现出较强的抗凋亡能力。分子机制的研究表明，EDAG可以通过某些途径活化转录因子 NF-kappaB，使其入核并激活其下游基因如c-myc，Bcl-2 及Bcl-xL等凋亡相关蛋白的表达。
酵母双杂交体系是一种采用分子遗传学手段、通过鉴定报告基因的转录活性检测蛋白质-蛋白质相互作用的方法。为深入研究EDAG基因激活NF-κB的机制，本研究以EDAG为诱饵蛋白，用酵母双杂交系统从人骨髓cDNA文库中筛选其相互作用蛋白，希望得到一些参与EDAG调控NF-kappaB通路的相互作用蛋白。
本实验分以下几个方面进行研究：
1．诱饵蛋白pGBKT7-EDAG的构建和鉴定
为了筛选EDAG的相互作用蛋白,本研究用PstⅠ和EcoRⅠ限制性内切酶对PMD-EDAG和pGBKT7载体进行酶切,将EDAG片段插入到pGBKT7载体中,获得诱饵蛋白pGBKT7-EDAG。
2．人骨髓文库中EDAG相互作用蛋白的筛选
利用酵母双杂交方法以1.0kb的EDAG作为诱饵蛋白，筛选在人骨髓细胞中能与EDAG有相互作用的蛋白，这些与EDAG有结合作用的蛋白可能是EDAG的特异性底物或者是在细胞内调节或介导EDAG功能的一些重要介导分子。通过对人骨髓文库的筛选，一共得到57个阳性克隆。发现几个重要的候选基因，他们编码的蛋白分别是：THAP11、ABP-280、IL8等。其中THAP11重复出现10次，本文对THAP-11的功能进
行了重点研究。其他相互作用分子ABP280、IL8的相关研究正在进行中。
3．THAP11对NF-κB的抑制及抑制EDAG对NF-κB的活化
通过GST-pulldown、co-IP（免疫共沉淀）验证EDAG同THAP-11的相互作用后，通过报道基因研究THAP11对EDAG调节NF-κB的影响。实验结果证明THAP11不仅抑制NF-κB的活性，而且抑制EDAG对NF-κB的活化作用，提示THAP11可能是EDAG调控NF-κB的重要参与蛋白。
4．人骨髓文库中THAP11相互作用蛋白的筛选
利用酵母双杂交方法以THAP11为诱饵蛋白，从人骨髓cDNA文库中用酵母双杂交系统筛选到其与G蛋白具有强烈的相互作用。G蛋白，比如Ras，也参与细胞的凋亡调控。
综上所述，本实验的主要结论是：THAP11是EDAG的重要相互作用蛋白，可能对EDAG的分子作用机制有重要的调控作用。THAP11可以抑制NF-κB的活性，而且可以抑制EDAG对NF-κB的活化作用。
EDAG (erythroid differentiation-associated gene), which is homologous to mouse hemogen and rat RP59, is identified from human fetal liver by using the polymerase chain reaction (PCR)-based subtractive hybridization method. EDAG exhibits specific expression in human hematopoietic tissues and cells, including adult bone marrow and fetal liver, and no EDAG transcripts are detected in adult liver, heart, brain, skeletal muscle, kidney, spleen, pancreas, tonsil, colon and peripheral blood mononuclear cells (PBMCs). Moreover, the expression of EDAG mRNA in leukemia cell lines K562 and MO7e is very high. When K562 cells are induced to differentiate toward erythroid or megakaryocytic phenotypes in response to hemin, erythropoietin (EPO) or pentahydroxytiglia myristate acetate (PMA), EDAG is quickly down-regulated in a time-dependent manner. Functionally, our previous study also show that the overexpression of EDAG in NIH3T3 cells results in malignant transformation of the cells characterized by cell morphology, anchorage-independent growth, and tumorigenicity in nude mice. EDAG gene is mapped to chromosome 9q22, a region that contains the break points of several hematopoietic neoplasms. Taken together, these data suggest that EDAG gene might play an important role in hematopoietic development and neoplasms.
Moreover, down-regulation of EDAG protein in K562 cells resulted in inhibition of growth and colony formation, and enhancement of sensitivity to erythroid differentiation induced by hemin. Overexpression of EDAG in HL-60 cells significantly blocked the expression of monocyte/macrophage differentiation marker CD11b after PMA induction. Moreover, overexpression of EDAG in pro-B Ba/F3 cells prolonged survival and ncreased the expression of c-Myc, Bcl-2 and Bcl-xL in absence of IL-3. Furthermore, we showed that EDAG enhance the transcriptional activity of NF-(B, and high DNA binding
activity of NF-(B was sustained in Ba/F3 cells after IL-3 withdrawn. Inhibition of NF-(B activity resulted in promoting Ba/F3 cells death. These results suggest that EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of NF-(B.
NF-B is present in the cytoplasm of the majority of cell types as homodimer or heterodimer of a family of structurally related proteins. Five members have been identified in mammalian cells: RelA (p65), cRel, RelB, NF-B1 (p50/p105), and NF-B2 (p52/p100). They are present in an inactive form associated with inhibitory proteins that mask their nuclear localization signal. Inhibitors belong either to the IB family (IB, , , and Bcl3) or are the precursors of NF-B1 and NF-B2: p105 and p100, respectively. A wide variety of stimuli are known to activate NF-B, including cytokines, growth factors, bacterial and viral products, oxidative stress, UV irradiation, and some pharmaceutical drugs and chemicals. Upon cell stimulation IB is rapidly phosphorylated at two conserved serine residues near its amino terminus. Similarly, p105 is phosphorylated in its carboxyl-terminal region. Phosphorylation of the inhibitors triggers their proteolytic degradation via the ubiquitin-proteasome pathway. De-repressed NF-kappa B proteins translocate to the nucleus, where they bind and transactivate kappa B sites within the promoter region of NF-kappa B-regulated genes. Many studies have shown that Rel/NF-kappa B transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. Constitutive activation of NF-(B occurs in cells transformed by several classical oncoproteins including Ras, Raf, chimerical BCR-ABL oncoproteins and transforming viral proteins such as HTLV, EBV etc. Although it has been previous reported that many types of hematopoietic neoplasms have
constitutive activation of NF-(B and this is a major distinguishing characteristic between normal and leukemia cells, the mechanism of increased NF- κB ac
前期研究表明，EDAG特异表达于造血组织与胚胎组织，并在白血病细胞中高表达。利用反义核酸技术抑制EDAG表达后，可以抑制白血病细胞的增殖能力以及诱导剂所诱导的分化能力。在细胞因子依赖的细胞株中高表达EDAG 可使细胞对细胞因子的依赖性降低，并表现出较强的抗凋亡能力。分子机制的研究表明，EDAG可以通过某些途径活化转录因子 NF-kappaB，使其入核并激活其下游基因如c-myc，Bcl-2 及Bcl-xL等凋亡相关蛋白的表达。
酵母双杂交体系是一种采用分子遗传学手段、通过鉴定报告基因的转录活性检测蛋白质-蛋白质相互作用的方法。为深入研究EDAG基因激活NF-κB的机制，本研究以EDAG为诱饵蛋白，用酵母双杂交系统从人骨髓cDNA文库中筛选其相互作用蛋白，希望得到一些参与EDAG调控NF-kappaB通路的相互作用蛋白。
本实验分以下几个方面进行研究：
1．诱饵蛋白pGBKT7-EDAG的构建和鉴定
为了筛选EDAG的相互作用蛋白,本研究用PstⅠ和EcoRⅠ限制性内切酶对PMD-EDAG和pGBKT7载体进行酶切,将EDAG片段插入到pGBKT7载体中,获得诱饵蛋白pGBKT7-EDAG。
2．人骨髓文库中EDAG相互作用蛋白的筛选
利用酵母双杂交方法以1.0kb的EDAG作为诱饵蛋白，筛选在人骨髓细胞中能与EDAG有相互作用的蛋白，这些与EDAG有结合作用的蛋白可能是EDAG的特异性底物或者是在细胞内调节或介导EDAG功能的一些重要介导分子。通过对人骨髓文库的筛选，一共得到57个阳性克隆。发现几个重要的候选基因，他们编码的蛋白分别是：THAP11、ABP-280、IL8等。其中THAP11重复出现10次，本文对THAP-11的功能进
行了重点研究。其他相互作用分子ABP280、IL8的相关研究正在进行中。
3．THAP11对NF-κB的抑制及抑制EDAG对NF-κB的活化
通过GST-pulldown、co-IP（免疫共沉淀）验证EDAG同THAP-11的相互作用后，通过报道基因研究THAP11对EDAG调节NF-κB的影响。实验结果证明THAP11不仅抑制NF-κB的活性，而且抑制EDAG对NF-κB的活化作用，提示THAP11可能是EDAG调控NF-κB的重要参与蛋白。
4．人骨髓文库中THAP11相互作用蛋白的筛选
利用酵母双杂交方法以THAP11为诱饵蛋白，从人骨髓cDNA文库中用酵母双杂交系统筛选到其与G蛋白具有强烈的相互作用。G蛋白，比如Ras，也参与细胞的凋亡调控。
综上所述，本实验的主要结论是：THAP11是EDAG的重要相互作用蛋白，可能对EDAG的分子作用机制有重要的调控作用。THAP11可以抑制NF-κB的活性，而且可以抑制EDAG对NF-κB的活化作用。
EDAG (erythroid differentiation-associated gene), which is homologous to mouse hemogen and rat RP59, is identified from human fetal liver by using the polymerase chain reaction (PCR)-based subtractive hybridization method. EDAG exhibits specific expression in human hematopoietic tissues and cells, including adult bone marrow and fetal liver, and no EDAG transcripts are detected in adult liver, heart, brain, skeletal muscle, kidney, spleen, pancreas, tonsil, colon and peripheral blood mononuclear cells (PBMCs). Moreover, the expression of EDAG mRNA in leukemia cell lines K562 and MO7e is very high. When K562 cells are induced to differentiate toward erythroid or megakaryocytic phenotypes in response to hemin, erythropoietin (EPO) or pentahydroxytiglia myristate acetate (PMA), EDAG is quickly down-regulated in a time-dependent manner. Functionally, our previous study also show that the overexpression of EDAG in NIH3T3 cells results in malignant transformation of the cells characterized by cell morphology, anchorage-independent growth, and tumorigenicity in nude mice. EDAG gene is mapped to chromosome 9q22, a region that contains the break points of several hematopoietic neoplasms. Taken together, these data suggest that EDAG gene might play an important role in hematopoietic development and neoplasms.
Moreover, down-regulation of EDAG protein in K562 cells resulted in inhibition of growth and colony formation, and enhancement of sensitivity to erythroid differentiation induced by hemin. Overexpression of EDAG in HL-60 cells significantly blocked the expression of monocyte/macrophage differentiation marker CD11b after PMA induction. Moreover, overexpression of EDAG in pro-B Ba/F3 cells prolonged survival and ncreased the expression of c-Myc, Bcl-2 and Bcl-xL in absence of IL-3. Furthermore, we showed that EDAG enhance the transcriptional activity of NF-(B, and high DNA binding
activity of NF-(B was sustained in Ba/F3 cells after IL-3 withdrawn. Inhibition of NF-(B activity resulted in promoting Ba/F3 cells death. These results suggest that EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of NF-(B.
NF-B is present in the cytoplasm of the majority of cell types as homodimer or heterodimer of a family of structurally related proteins. Five members have been identified in mammalian cells: RelA (p65), cRel, RelB, NF-B1 (p50/p105), and NF-B2 (p52/p100). They are present in an inactive form associated with inhibitory proteins that mask their nuclear localization signal. Inhibitors belong either to the IB family (IB, , , and Bcl3) or are the precursors of NF-B1 and NF-B2: p105 and p100, respectively. A wide variety of stimuli are known to activate NF-B, including cytokines, growth factors, bacterial and viral products, oxidative stress, UV irradiation, and some pharmaceutical drugs and chemicals. Upon cell stimulation IB is rapidly phosphorylated at two conserved serine residues near its amino terminus. Similarly, p105 is phosphorylated in its carboxyl-terminal region. Phosphorylation of the inhibitors triggers their proteolytic degradation via the ubiquitin-proteasome pathway. De-repressed NF-kappa B proteins translocate to the nucleus, where they bind and transactivate kappa B sites within the promoter region of NF-kappa B-regulated genes. Many studies have shown that Rel/NF-kappa B transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. Constitutive activation of NF-(B occurs in cells transformed by several classical oncoproteins including Ras, Raf, chimerical BCR-ABL oncoproteins and transforming viral proteins such as HTLV, EBV etc. Although it has been previous reported that many types of hematopoietic neoplasms have
constitutive activation of NF-(B and this is a major distinguishing characteristic between normal and leukemia cells, the mechanism of increased NF- κB ac
引文
Lu J, Xu WX, Wang SY, Zhan YQ, Jiang Y, Cai WM, Yang XM. Isolation and Characterization of EDAG-1, A Novel Gene Related to Regulation in Hematopoietic System. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2001, 33(6):641-646
Yang LV, Nicholson RH, Kaplan J, et al. Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms. Mech Dev. 2001, 104:105-111
Yang LV, Heng HH, Wan JM, et al. Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Dev Dyn. 2003, 228:606-616
Lu J, Xu WX, Wang SY, Jiang Y, Li CY, Cai WM, Yang XM. Overexpression of EDAG-1 in NIH3T3 cells leads to malignant transformation. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002, 34(1):95-98
Li CY, Lv J, Zhan YQ, et al. EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of Nuclear Factor-κB. Mol Cell Biol. 2004, in submitted
Pahl HL. Activators and target genes of Rel/NF-κB transcription facrors. Oncogene. 1999, 18:6853-6866
May MJ, Ghosh S. Signal transduction through NF-κB. Immunol Today. 1998, 19:80-88
Baeuerle PA, Baltimore D. NF-κB: ten years after. Cell. 1996, 87:13-20
Baeuerle PA, Rupec RA, Pahl HL. Reactive oxygen intermediates as second messengers of a general pathogen response. Pathol Biol. 1996, 44:29-35
Karin M, Ben-Neriah Y. Phosphorylation meets ubquitination: the control of NF-κB activity. Annu Rev Immunol. 2000, 18:621-663
Silverman N, Maniatis T. NF-κB signal pathways in mammalian and insect innate immunity. Genes Dev. 2001, 15:2321-2342
Baldwin AS. Series introduction: The transcription factor NF-κB and human disease. J Clin Invest. 2001, 107:3-6
Tak PP, Firestein GS. NF-κB: a key role in inflammatory disease. J Clin Invest. 2001, 107:7-11
Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest. 2001, 107:241-246
Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell. 2002, 109:S81-S96
Sakurai H, Suzuki S, Kawasaki N, et al. Tumor necrosis factor-a-induced IKK phosphorylation of NF-κB p65 on serine is mediated through the TRAF2, TRAF5, and TAK1 signal pathway. J Biol Chem. 2003, 278(38):36916-36923
Lan V, Pham AT, Tamayo L, et al. Inhibition of constitutive NF-κB activition in mantle cell lymphoma B cell leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003, 171:88-95
Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001, 11:372-277
Karin M, Lin A. NF-κB at the crossroads of life and death. Nat Immunol. 2002, 3(3):221-227
Roussigne M, Kossida S, Lavigne AC, et al. The THAP domain: a novel protein motif with similarity to the DNA-binding domain of P element transposase. Trends Biochem Sci. 2003, 28(2): 66-69
Bhaskar V. A functional interaction between dorsal and components of the smt3 conjugation machinery. J. Biol. Chem. 2000, 275:4033-4040
Michael GJR, Blakely CM, Hopkins DA, et al. Regulation of interferon-induced protein kinase PKR: Modulation of p58IPK inhibitory function by a novel protein, P52rIPK. Mol Cell Biol. 1998, 18(2):859-871
Melville MW, Hansen WJ, Freeman BC, et al. The molecular chaperone,hsp40, regulates the activity of p58IPK, the cellular inhibitor of PKR. Proc Natl Acad Sci.USA. 1997, 94:97-102
Gale MJ, Jr SL, Tan M, et al. Interaction of the interferon-induced PKR protein kinase with inhibitory protein p58IPK and vaccinia virus K3L is unique domains: implications for kinase regulation. Mol Cell Biol. 1996, 16:4172-4181
Kumar A, Yang Y, Flati V, et al. Deficient cytokine signaling in mouse embro fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-κB. EMBO J. 1997, 16:406-413
Der SD, Yang YL, Weissman C, et al. A double stranded RNA activated protein kinase- dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci.USA. 1997, 94: 3279-3283
Hinnebusch AG. The eIF-2α kinases: regulators of protein synthesis in starvation and stress. Semin Cell Biol. 1994, 5:417-426
Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4(Par-4) to PML nuclear bodies. Oncogene. 2003, 22:2432-2442
Guo A, Salomoni P, Luo H, et al. The function of PML in p53-dependent apoptosis. Nat Cell Biol. 2000, 2:730-736
Mattson MP, Duan W, Chan SL. Genetic aberrancies and neurodegenerative disorders. J Mol Neurosci. 1999, 13:17-30
Richard DJ, Schumacher V, Royer-Pokora B, et al. Par4 is a coactivator for a splice isoform -specific transcriptional activation domain in WT1. Genes Dev. 2001, 15:328-339
Lee CC. DNA binding by the KP repressor protein inhibits P element transposase activity in vitro. EMBO J. 1998, 17:4166-4174
Qiu G, Ahmed M, Sells SF, et al. Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. Oncogene. 1999, 18:623-631
Ibrado AM, Huang Y, Fang G, et al. Bcl-xL overexpression inhibits taxol-induced Yama protease activity and apoptosis. Cell Growth Differ. 1996, 7(8):1087-1090
Yang LV, Nicholson RH, Kaplan J, et al. Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms. Mech Dev. 2001, 104:105-111
Yang LV, Heng HH, Wan JM, et al. Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Dev Dyn. 2003, 228:606-616
Lu J, Xu WX, Wang SY, Jiang Y, Li CY, Cai WM, Yang XM. Overexpression of EDAG-1 in NIH3T3 cells leads to malignant transformation. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002, 34(1):95-98
Li CY, Lv J, Zhan YQ, et al. EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of Nuclear Factor-κB. Mol Cell Biol. 2004, in submitted
Pahl HL. Activators and target genes of Rel/NF-κB transcription facrors. Oncogene. 1999, 18:6853-6866
May MJ, Ghosh S. Signal transduction through NF-κB. Immunol Today. 1998, 19:80-88
Baeuerle PA, Baltimore D. NF-κB: ten years after. Cell. 1996, 87:13-20
Baeuerle PA, Rupec RA, Pahl HL. Reactive oxygen intermediates as second messengers of a general pathogen response. Pathol Biol. 1996, 44:29-35
Karin M, Ben-Neriah Y. Phosphorylation meets ubquitination: the control of NF-κB activity. Annu Rev Immunol. 2000, 18:621-663
Silverman N, Maniatis T. NF-κB signal pathways in mammalian and insect innate immunity. Genes Dev. 2001, 15:2321-2342
Baldwin AS. Series introduction: The transcription factor NF-κB and human disease. J Clin Invest. 2001, 107:3-6
Tak PP, Firestein GS. NF-κB: a key role in inflammatory disease. J Clin Invest. 2001, 107:7-11
Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest. 2001, 107:241-246
Ghosh S, Karin M. Missing pieces in the NF-κB puzzle. Cell. 2002, 109:S81-S96
Sakurai H, Suzuki S, Kawasaki N, et al. Tumor necrosis factor-a-induced IKK phosphorylation of NF-κB p65 on serine is mediated through the TRAF2, TRAF5, and TAK1 signal pathway. J Biol Chem. 2003, 278(38):36916-36923
Lan V, Pham AT, Tamayo L, et al. Inhibition of constitutive NF-κB activition in mantle cell lymphoma B cell leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003, 171:88-95
Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001, 11:372-277
Karin M, Lin A. NF-κB at the crossroads of life and death. Nat Immunol. 2002, 3(3):221-227
Roussigne M, Kossida S, Lavigne AC, et al. The THAP domain: a novel protein motif with similarity to the DNA-binding domain of P element transposase. Trends Biochem Sci. 2003, 28(2): 66-69
Bhaskar V. A functional interaction between dorsal and components of the smt3 conjugation machinery. J. Biol. Chem. 2000, 275:4033-4040
Michael GJR, Blakely CM, Hopkins DA, et al. Regulation of interferon-induced protein kinase PKR: Modulation of p58IPK inhibitory function by a novel protein, P52rIPK. Mol Cell Biol. 1998, 18(2):859-871
Melville MW, Hansen WJ, Freeman BC, et al. The molecular chaperone,hsp40, regulates the activity of p58IPK, the cellular inhibitor of PKR. Proc Natl Acad Sci.USA. 1997, 94:97-102
Gale MJ, Jr SL, Tan M, et al. Interaction of the interferon-induced PKR protein kinase with inhibitory protein p58IPK and vaccinia virus K3L is unique domains: implications for kinase regulation. Mol Cell Biol. 1996, 16:4172-4181
Kumar A, Yang Y, Flati V, et al. Deficient cytokine signaling in mouse embro fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-κB. EMBO J. 1997, 16:406-413
Der SD, Yang YL, Weissman C, et al. A double stranded RNA activated protein kinase- dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci.USA. 1997, 94: 3279-3283
Hinnebusch AG. The eIF-2α kinases: regulators of protein synthesis in starvation and stress. Semin Cell Biol. 1994, 5:417-426
Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4(Par-4) to PML nuclear bodies. Oncogene. 2003, 22:2432-2442
Guo A, Salomoni P, Luo H, et al. The function of PML in p53-dependent apoptosis. Nat Cell Biol. 2000, 2:730-736
Mattson MP, Duan W, Chan SL. Genetic aberrancies and neurodegenerative disorders. J Mol Neurosci. 1999, 13:17-30
Richard DJ, Schumacher V, Royer-Pokora B, et al. Par4 is a coactivator for a splice isoform -specific transcriptional activation domain in WT1. Genes Dev. 2001, 15:328-339
Lee CC. DNA binding by the KP repressor protein inhibits P element transposase activity in vitro. EMBO J. 1998, 17:4166-4174
Qiu G, Ahmed M, Sells SF, et al. Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. Oncogene. 1999, 18:623-631
Ibrado AM, Huang Y, Fang G, et al. Bcl-xL overexpression inhibits taxol-induced Yama protease activity and apoptosis. Cell Growth Differ. 1996, 7(8):1087-1090