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Binding of p53 to the KIX domain of CREB binding protein - A potential link to human t-cell leukemia virus, type I-associated leukemogenesis

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JOURNAL OF BIOLOGICAL CHEMIStRY 1999年第37期274卷 26321-26328页

作者： Van Orden, K Giebler, HA Lemasson, I Gonzales, M Nyborg, JK Colorado State Univ Dept Biochem & Mol Biol Ft Collins CO 80523 USA

the pleiotropic cellular coactivator CREB binding protein (CBP) plays a critical role in supporting p53-dependent tumor suppressor functions. p53 has been shown to directly interact with a carboxyl-terminal region of CBP for recruitment of the coactivator to p53-responsive genes. In this report, we identify the KM domain as a new p53 contact point on CBP. We show that both recombinant and endogenous forms of p53 specifically interact with KM. We demonstrate that the activation domain of p53 participates in KM binding and provide evidence showing that this interaction is critical for p53 transactivation function. the human t-cell leukemia virus, type-I-encoded oncoprotein tax is a well established repressor of p53 transcription function. Like p53, tax also binds to KIX. the finding that both transcription factors bind to a common region of CBP suggests that coactivator competition may account for the observed repression. We demonstrate reciprocal repression between tax and p53 in transient transfection assays, supporting the idea of intracellular coactivator competition. We biochemically confirm coactivator competition by directly showing that both transcription factors bind to KM in a mutually exclusive fashion. these data provide molecular evidence for the observed intracellular competition and suggest that tax inhibits p53 function by abrogating a novel p53-KIX interaction. thus, tax competition for the p53-KIX complex may be a pivotal event in the human t-cell leukemia virus, type I transformation pathway.

关键词：结合竞争性 CREB结合蛋白质克隆分子基因产物 tax/代谢人类嗜t淋巴细胞病毒1型/生理学 Jurkat细胞白血病 t细胞/病毒学核蛋白质类/遗传学核蛋白质类/代谢蛋白质结合重组融合蛋白质类/遗传学重组融合蛋白质类/代谢反式激活因子类/遗传学反式激活因子类/代谢肿瘤抑制蛋白质p53/代谢人类

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Evidence for specific nucleocytoplasmic transport pathways used by leucine-rich nuclear export signals

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PROCEEDINGS OF tHE NAtIONAL ACADEMY OF SCIENCES OF tHE UNItED StAtES OF AMERICA 1999年第11期96卷 6229-6234页

作者： Elfgang, C Rosorius, O Hofer, L Jaksche, H Hauber, J Bevec, D Novartis Res Inst Dept Immunol A-1235 Vienna Austria Univ Erlangen Nurnberg Inst Clin & Mol Virol D-91054 Erlangen Germany

Various proteins with different biological activities have been observed to be translocated from the nucleus to the cytoplasm in an energy- and signal-dependent manner in eukaryotic cells. this nuclear export is directed by nuclear export signals (NESs), typically characterized by hydrophobic, primarily leucine, amino acid residues. Moreover, it has been shown that CRM1/exportin I is an export receptor for leucine-rich NESs. However, additional NES-interacting proteins have been described. In particular, eukaryotic initiation factor 5A (eIF-5A) has been shown to be a critical cellular cofactor for the nuclear export of the HIV type 1 (HIV-I) Rev trans-activator protein. In this study we compared the nuclear export activity of NESs of different origin. Microinjection of export substrates into the nucleus of somatic cells in combination with specific inhibitors indicated that specific nuclear export pathways exist for different NES-containing proteins. In particular, inhibition of eIF-5A blocked the nuclear export of NESs derived from the HIV-1 Rev and human t cell leukemia virus type I Rex transactivators, whereas nucleocytoplasmic translocation of the protein kinase inhibitor-NES was unaffected. In contrast, however, inhibition of CRM/exportin 1 blocked the nuclear export of all NES-containing proteins investigated. Our data confirm that CRM1/exportin 1 is a general export receptor for leucine-rich NESs and suggest that eIF-5A acts either upstream of CRM1/exportin 1 or forms a complex with the NES and CRM1/exportin 1 in the nucleocytoplasmic translocation of the HIV-1 Rev and human t cell leukemia virus type I Rex RNA export factors.

关键词：氨基酸序列载体蛋白质类/拮抗剂和抑制剂载体蛋白质类/化学载体蛋白质类/代谢细胞核/代谢克隆分子细胞质/代谢基因产物 rev/代谢谷胱甘肽转移酶/代谢 HIV-1/生理学 HeLa细胞人类嗜t淋巴细胞病毒1型/生理学核胞浆转运蛋白类亮氨酸微量注射模型生物学分子序列数据核蛋白质类/代谢肽起始因子类/代谢 RNA结合蛋白质类受体胞质和核重组融合蛋白质类/代谢信号传导 rev基因产物人免疫缺陷病毒人类

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Increased HtLV-I proviral load and preferential expansion of HtLV-I tax-specific CD8⁺ t cells in cerebrospinal fluid from patients with HAM/tSP

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ANNALS OF NEUROLOGY 2001年第6期50卷 807-812页

作者： Nagai, M Yamano, Y Brennan, MB Mora, CA Jacobson, S NINCDS Viral Immunol Sect Neuroimmunol Branch NIH Bethesda MD 20892 USA

to date, high human t-cell lymphotropic virus type I proviral load in patients with human t-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis has been reported and is thought to be related to the pathogenesis of human t-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. However, the proviral load in cerebrospinal. fluid has not been well investigated. We measured human t-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells from human t-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis patients using real-time quantitative polymerase chain reaction (taqMan). Human t-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells were significantly higher than that of the matched peripheral blood mononuclear cells, and a high ratio of human t-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells to peripheral blood mononuclear cells were observed in patients with short duration of illness. Human t-cell lymphotropic virus type I tax-specific CD8(+) t cells, as detected by peptide-loaded HLA tetramers, accumulated in cerebrospinal fluid compared with that in peripheral blood mononuclear cells, while the frequency of cytomegalovirus-specific CD8(+) t cells in cerebrospinal fluid was reduced. these observations suggest that accumulation of both human t-cell lymphotropic virus type I-infected cells and preferential expansion of human t-cell lymphotropic virus type I-specific CD8(+) cells in cerebrospinal fluid may play a role in the pathogenesis of human t-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

关键词：生物学标记 CD8阳性t淋巴细胞/病毒学脑脊髓液/细胞学脑脊髓液/病毒学流式细胞术基因产物 tax/代谢人类嗜t淋巴细胞病毒1型/生理学轻截瘫热带痉挛性/脑脊髓液轻截瘫热带痉挛性/免疫学轻截瘫热带痉挛性/病毒学肽碎片/代谢病毒载量青少年成年人女(雌)性人类男(雄)性中年人

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Cell type-specific E2F activation and cell cycle progression induced by the oncogene product tax of human t-cell leukemia virus type I

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JOURNAL OF BIOLOGICAL CHEMIStRY 2000年第15期275卷 11154-11163页

作者： Ohtani, K Iwanaga, R Arai, M Huang, YP Matsumura, Y Nakamura, M Tokyo Med & Dent Univ Sch Med Human Gene Sci Ctr Bunkyo Ku Tokyo 1138510 Japan Tokyo Med & Dent Univ Sch Med Dept Microbiol Bunkyo Ku Tokyo 1138510 Japan

the transactivator protein tax of human t-cell leukemia virus type I plays an important role in the development of adult t-cell leukemia probably through modulation of growth regulatory molecules including p16(INK4a). the molecular mechanism of leukemogenesis induced by tax has yet to be elucidated. We analyzed tax function in the cell cycle using an interleukin-2 (IL-2)-dependent human t-cell line (Kit 225) that can undergo cell cycle arrest at G(0)/G(1) phase by deprivation of IL-2. tax activated endogenous E2F activity in EL-2-starved Kit 225 cells, resulting in activation of E2F site-carrying promoters of genes involved in G(1) to S phase transition in a cell type-dependent and p16(INK4a)-independent manner, the ability of tax mutants to activate E2F coincided with that to activate nuclear factors KB and At, sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F, Introduction of tax by a recombinant adenovirus induced cell cycle progression to G(2)/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression, Similarly, tax-induced cell cycle progression was seen with peripheral blood lymphocytes prestimulated with phytohemagglutinin, Analyses with tax mutants did not allow tax-induced cell cycle progression to be differentiated from tax-dependent activation of E2F, suggesting that tax induces cell cycle progression presumably through activation of E2F. Nevertheless, infection with an E2F1-expressing virus, which is sufficient for induction of S phase in serum-starved fibroblasts, was not sufficient for either E2F activation or cell cycle progression in IL-2-starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in t-cells that is activated by tax.

关键词：结合部位载体蛋白质类细胞周期细胞周期蛋白质类细胞系细胞周期蛋白D2 细胞周期蛋白类/遗传学 DNA结合蛋白质类 E2F转录因子类 E2F1转录因子基因表达调控基因产物 tax/生理学基因 p16/生理学人类嗜t淋巴细胞病毒1型/生理学白细胞介素2/生理学 NF-κB/生理学视网膜母细胞瘤结合蛋白1 转录因子DP1 转录因子/生理学人类

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Constitutive activation of transcription factor AP-1 in primary adult t-cell leukemia cells

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BLOOD 2000年第12期95卷 3915-3921页

作者： Mori, N Fujii, M Iwai, K Ikeda, S Yamasaki, Y Hata, t Yamada, Y tanaka, Y tomonaga, M Yamamoto, N Nagasaki Univ Inst Trop Med Dept Prevent Med & AIDS Res Nagasaki 8528523 Japan Nagasaki Univ Sch Med Dept Lab Med Nagasaki 852 Japan Nagasaki Univ Sch Med Inst Atom Dis Dept Hematol Nagasaki 852 Japan City Sasebo Gen Hosp Dept Internal Med Sasebo Japan Kokura Mem Hosp Dept Internal Med Kitakyushu Fukuoka Japan Univ Ryukyus Fac Med Okinawa Asia Res Ctr Med Sci Dept Immunol & Infect Dis Okinawa Japan Niigata Univ Sch Med Dept Virol Niigata Japan

Human t-cell leukemia virus type-I (HtLV-I) is the etiologic agent of adult t-cell leukemia (AtL), this study examined the status of the oncogenic transcription factor AP-1 in leukemic cells freshly isolated from patients with AtL, Leukemic cells from peripheral blood of all patients with AtL exhibited constitutive AP-1 DNA binding activity, whereas mononuclear cells from normal individuals did not. In agreement with previous studies, HtLV-I transforming protein, tax, was found to stimulate the DNA binding activity of AP-1 in a t-cell line. However, HtLV-I genes, including fax, were not significantly expressed in leukemic cells freshly obtained from patients with AtL, Moreover, all t-cell lines derived from leukemic cells of patients with AtL also displayed constitutive AP-1 DNA binding activity, but expressed little tax protein. thus, leukemic cells of patients with AtL appear to have tax-independent mechanisms that induce AP-1 activity, both in vivo and in vitro. In antibody supershift experiments, AP-1 in fresh leukemic cells and AtL-derived cell lines were found to contain JunD, Consistently, all primary AtL cells and AtL-derived cell lines expressed high levels of JunD messenger RNA. Our results suggest that AP-1 is activated in leukemic cells of patients with AtL through a tax-independent mechanism and this may play a role in the deregulated phenotypes of AtL leukemic cells, (C) 2000 by the American Society of Hematology.

关键词：细胞系细胞核/代谢基因表达调控基因产物 tax/代谢基因 jun 基因 pX 人类嗜t淋巴细胞病毒1型/遗传学人类嗜t淋巴细胞病毒1型/生理学 Jurkat细胞原癌基因蛋白质c-jun/代谢 t淋巴细胞/代谢 t淋巴细胞/病毒学反式激活(遗传学) 转录因子AP-1/代谢转染肿瘤细胞培养的成年人人类

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Arsenic-interferon-α-triggered apoptosis in HtLV-I transformed cells is associated with tax down-regulation and reversal of NF-κB activation

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BLOOD 2000年第8期96卷 2849-2855页

作者： El-Sabban, ME Nasr, R Dbaibo, G Hermine, O Abboushi, N Quignon, F Ameisen, JC Bex, F de thé, H Bazarbachi, A Amer Univ Beirut Fac Med Dept Human Morphol Beirut Lebanon Amer Univ Beirut Fac Med Dept Internal Med Beirut Lebanon Amer Univ Beirut Fac Med Dept Biochem Beirut Lebanon Amer Univ Beirut Fac Med Dept Pediat Beirut Lebanon Hop Necker Enfants Malad Dept Hematol Paris France Univ Paris 07 Hop St Louis UPR 9051 CNRS Lab Comite Paris Ligue Contre Canc 11 Paris France Hop Bichat Claude Bernard INSERM CJF 9701 F-75877 Paris France Free Univ Brussels Dept Mol Biol Brussels Belgium

Human t-cell lymphotropic virus type I (HtLV-I)-associated adult t-cell leukemia/lymphoma (AtL) is a malignancy of mature activated t cells resistant to conventional chemotherapy, the viral transactivator protein tax plays a critical role in HtLV-C induced transformation and apoptosis resistance by inducing I kappaB-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HtLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bar, or p53 expression. However, combined As and IFN induce the degradation of tax, associated with an up-regulation of I kappaB-alpha resulting in a sharp decrease in ReIA DNA binding nuclear factor (NF)-kappaB complexes because of the cytoplasmic retention of ReIA, taken the role of tax in HtLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappaB pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-or in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in AtL patients. (C) 2000 by the American Society of Hematology.

关键词：细胞凋亡/药物作用砷剂/药理学半胱氨酸天冬氨酸蛋白酶/生理学细胞周期/药物作用细胞系转化细胞转化病毒/药物作用 DNA/代谢 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢药物协同作用酶激活基因表达调控白血病/药物作用基因表达调控病毒/药物作用基因产物 tax/生理学人类嗜t淋巴细胞病毒1型/生理学 I-κB蛋白质类干扰素α/药理学连接酶类/代谢大分子物质 NF-κB/代谢肿瘤蛋白质类/生理学氧化物/药理学 t淋巴细胞/代谢 t淋巴细胞/病毒学反式激活(遗传学)/药物作用肿瘤细胞培养的人类

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Identification of a novel bovine serum protein which is involved in human t-cell leukemia virus type I (HtLV-I)-induced syncytium formation

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ARCHIVES OF VIROLOGY 1999年第1期144卷 1-18页

作者： Okuma, K Nakamura, M Nakano, S tanaka, Y Niho, Y Kyushu Univ Fac Med Dept Internal Med 1 Fukuoka 8128582 Japan Kitasato Univ Sch Sci Dept Biosci Sagamihara Kanagawa Japan

By immunizing rats with cocultured HtLV-I-positive ILt8M2 and HtLV-I-negative MOLt-4 cells, we isolated a monoclonal antibody (mAb), designated as mAb R21, which enhances the syncytium formation induced by coculturing ILt8M2 cells with MOLt-4 cells. the antigen recognized by mAb R21 was found on the surface of all t-cell, fibroblastoid, and epithelial cell lines, and a part of B-cell and myelomonocytoid cell lines. MAb R21 reacted with an approximately 17-kDa protein from ILt8M2 and MOLt-4 cell lysates in both nonreducing and reducing conditions by immunoblotting. Immunoprecipitation experiments using surface-labeled cells revealed that a 17-kDa protein is present on the surface of both ILt8M2 and MOLt-4 cells. Since the enhancing activity by mAb R21 of syncytium formation was observed only in the presence of a factor contained in fetal calf serum (FCS) which seems to bind to mAb R21, we purified this serum factor from FCS using a mAb R21- coupled Sepharose 4B column. the purified protein, designated as R21 protein, was revealed to be O-glycosylated but not N-glycosylated protein of approximately 17 kDa. the partial amino acid sequence of this protein indicates that R21 protein is a novel bovine serum protein which has approximately 90% amino acid homology with bovine platelet factor 4, a member of CXC chemokine family. these results indicate that the R21 protein on the surface of cells and/or in FCS may play an important role in the process of HtLV-I-induced syncytium formation by as yet unknown mechanism.

关键词：氨基酸序列抗体单克隆血蛋白质类/生理学人类嗜t淋巴细胞病毒1型/生理学白血病 t细胞/代谢白血病 t细胞/病理学白血病 t细胞/病毒学分子序列数据血小板因子4/遗传学序列比对序列同源性氨基酸肿瘤细胞培养的病毒复制动物牛人类大鼠

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