朱卫国
长期从事肿瘤分子生物学研究,在肿瘤的发生机制研究和肿瘤治疗学的基础研究中取得了较好的成绩
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- 姓名:朱卫国
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学术头衔:
博士生导师, 国家杰出青年科学基金获得者
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学科领域:
声学
- 研究兴趣:长期从事肿瘤分子生物学研究,在肿瘤的发生机制研究和肿瘤治疗学的基础研究中取得了较好的成绩
朱卫国,男,1962年9月出生。北京大学基础医学院生物化学与分子生物学系教授,博士生导师。国家杰出青年基金获得者. 美国癌症学会会员,科学学会会员,放射生物学会会员,NY科学学会特聘会员。World Journal of Gastroenterology 和 Chinese Journal of Biochemistry and Molecular Biology编委。 北京大学基础医学院党委书记, 生物化学与分子生物学系科研主任,基础医学院学术委员会委员,北京大学衰老中心学术副主任委员,北京大学糖尿病中心学术委员会委员。
长期从事肿瘤分子生物学研究,在肿瘤的发生机制研究和肿瘤治疗学的基础研究中取得了较好的成绩。主要研究方向是表观遗传学(甲基化和组蛋白修饰)对肿瘤发生的机制研究以及表观遗传去甲基化药物导致的DNA损伤修复的研究。在表观遗传学机制研究中,近5年来有多方面的研究贡献如(a) DNA甲基化导致基因失活的机制不在于其甲基化本身对转录因子结合的抑制,而在于可能是染色质构型受甲基化的影响所致,基于这一观点发表在国际较有影响的杂志上多篇文章受到同行的重视如:直接证明了DNA甲基化对特定转录因子的结合不受影响(Mol Cell Biol., 2003); 基因的启动子区域没有甲基化同样会引起基因表达失活 (Oncogene, 2001);松散染色质后转录因子可自由结合到甲基化的启动子中。(b) 阐明了蛋白质本身的修饰对基因表达的影响是表观遗传的研究的重要作用方式之一,如p53 的特定位点的乙酰化修饰会导致p53对下游基因p21启动子的特异结合和表达 (Mol Cell Biol, 2006). MTH2与PCNA的结合在紫外线作用下受特异位点乙酰化的影响而发生泛素化从而起修复DNA损伤的作用。(c) 在国际上首次报道和建立了去甲基化药物-核苷衍生物(5-氮脱氧胞苷,DNA去甲化制剂)和去组蛋白乙酰化酶抑制剂广泛诱导肿瘤细胞凋亡的模型 (Cancer Res, 2001, Current Medicinal Chemistry, 2003)。并证实去甲基化药物的主要作用可能在于其DNA损伤作用 (J. Biol. Chem., 2004), 与组蛋白去乙酰化酶的协同导致肿瘤细胞凋亡的机制可能在于DNA损伤的修复受到抑制的结果。
在国际知名杂志发表论文近30篇(第一作者和通讯作者12篇),其中影响因子大于6的有12篇,主要论文近年来被他人引用达350余次。
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【期刊论文】5-aza-2'-deoxycytidine activates the p53/p21Waf1/Cip1 pathway to inhibit cell proliferation
朱卫国, Wei-Guo Zhu‡, ¶, *, Theresa Hileman║, Yang Ke¶, Peichang Wang‡, Shaoli Lu‡, Wenrui Duan║, Zunyan Dai§, Tanjun Tong‡, Miguel A. Villalona-Calero║, Christoph Plass§ and Gregory A. Otterson║*
,-0001,():
-1年11月30日
In addition to its demethylating function, 5-aza-2'-deoxycytidine (5-aza-CdR) also plays an important role in inducing cell cycle arrest, differentiation and cell death. However, the mechanism by which 5-aza-CdR induces antineoplastic activity is not clear. In this study, we found that 5-aza-CdR at limited concentrations (0.01-5
5-aza-2', -deoxycytidine, demethylation, p21Waf1/, Cip1, p53, inhibition of cell proliferation, DNA damage
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朱卫国, Wei Xie, Peng Jiang, Lin Miao, Ying Zhao, Zhai Zhimin, Li Qing, Wei-guo Zhu and Mian Wu*
2046-2055 Nucleic Acids Research, 2006, Vol. 34, No.7,-0001,():
-1年11月30日
Deregulated expression of E2F1 not only promotes S-phase entry but also induces apoptosis. Although it has been well documented that E2F1 is able to induce p53-dependent apoptosis via raising ARF activity, the mechanism by which E2F induces p53-independent apoptosis remains unclear. Here we report that E2F1 can directly bind to and activate the promoter of Smac/DIABLO, a mitochondrial proapoptotic gene, through the E2F1-binding sites BS2 (-542~-535 bp) and BS3 (-200~-193 bp). BS2 and BS3 appear to be utilized in combination rather than singly by E2F1 in activation of Smac/DIABLO. Activation of BS2 and BS3 are E2F1-specific, since neither E2F2 nor E2F3 is able to activate BS2 or BS3. Using the H1299 ER-E2F1 cell line where E2F1 activity can be conditionally induced, E2F1 has been shown to upregulate the Smac/DIABLO expression at both mRNA and protein levels upon 4-hydroxytamoxifen treatment, resulting in an enhanced mitochondria-mediated apoptosis. Reversely, reducing the Smac/DIABLO expression by RNA interference significantly diminishes apoptosis induced by E2F1. These results may suggest a novel mechanism by which E2F1 promotes p53-independent apoptosis through directly regulating its downstream mitochondrial apoptosis-inducing factors, such as Smac/DIABLO.
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【期刊论文】Methylation of Adjacent CpG Sites Affects Sp1/Sp3 Binding and Activity in the p21Cip1 Promoter
朱卫国, Wei-Guo Zhu, , Kanur Srinivasan, Zunyan Dai, Wenrui Duan, Lawrence J. Druhan, Haiming Ding, Lisa Yee, Miguel A. Villalona-Calero, Christoph Plass, and Gregory A. Otterson*
MOLECULAR AND CELLULAR BIOLOGY, June 2003, p. 4056-4065,-0001,():
-1年11月30日
DNA methylation in the promoter of certain genes is associated with transcriptional silencing. Methylation affects gene expression directly by interfering with transcription factor binding and/or indirectly by recruiting histone deacetylases through methyl-DNA-binding proteins. In this study, we demonstrate that the human lung cancer cell line H719 lacks p53-dependent and -independent p21Cip1 expression. p53 response to treatment with gamma irradiation or etoposide is lost due to a mutation at codon 242 of p53 (C3W). Treatment with depsipeptide, an inhibitor of histone deacetylase, was unable to induce p53-independent p21Cip1 expression because the promoter of p21Cip1 in these cells is hypermethylated. By analyzing luciferase activity of transfected p21Cip1 promoter vectors, we demonstrate that depsipeptide functions on Sp1-binding sites to induce p21Cip1 expression. We hypothesize that hypermethylation may interfere with Sp1/Sp3 binding. By using an electrophoretic mobility shift assay, we show that, although methylation within the consensus Sp1-binding site did not reduce Sp1/Sp3 binding, methylation outside of the consensus Sp1 element induced a significant decrease in Sp1/Sp3 binding. Depsipeptide induced p21Cip1 expression was reconstituted when cells were pretreated with 5-aza-2α-deoxycytidine. Our data suggest, for the first time, that hypermethylation around the consensus Sp1-binding sites may directly reduce Sp1/Sp3 binding, therefore leading to a reduced p21Cip1 expression in response to depsipeptide treatment.
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朱卫国, Ying Zhao, , Shaoli Lu, Lipeng Wu, Guolin Chai, Haiying Wang, Yingqi Chen, Jia Sun, Yu Yu, Wen Zhou, Quanhui Zheng, Mian Wu, Gregory A. Otterson, and Wei-Guo Zhu*
MOLECULAR AND CELLULAR BIOLOGY, Apr. 2006, p. 2782-2790,-0001,():
-1年11月30日
Generally, histone deacetylase (HDAC) inhibitor-induced p21Waf1/Cip1 expression is thought to be p53 independent. Here we found that an inhibitor of HDAC, depsipeptide (FR901228), but not trichostatin A (TSA), induces p21Waf1/Cip1 expression through both p53 and Sp1/Sp3 pathways in A549 cells (which retain wild-type p53). This is demonstrated by measuring relative luciferase activities of p21 promoter constructs with p53 or Sp1 binding site mutagenesis and was further confirmed by transfection of wild-type p53 into H1299 cells (p53 null). That p53 was acetylated after depsipeptide treatment was tested by sequential immunoprecipitation/Western immunoblot analysis with anti-acetylated lysines and anti-p53 antibodies. The acetylated p53 has a longer half-life due to a significant decrease in p53 ubiquitination. Further study using site-specific antiacetyllysine antibodies and transfection of mutated p53 vectors (K319/K320/K321R mutated and K373R/K382R mutations) into H1299 cells revealed that depsipeptide specifically induces p53 acetylation at K373/K382, but not at K320. As assayed by coimmunoprecipitation, the K373/K382 acetylation is accompanied by a recruitment of p300, but neither CREB-binding protein (CBP) nor p300/CBP-associated factor (PCAF), to the p53 C terminus. Furthermore, activity associated with the binding of the acetylated p53 at K373/K382 to the p21 promoter as well as p21Waf1/Cip1 expression is significantly increased after depsipeptide treatment, as tested by chromatin immunoprecipitations and Western blotting, respectively. In addition, p53 acetylation at K373/K382 is confirmed to be required for recruitment of p300 to the p21 promoter, and the depsipeptide-induced p53 acetylation at K373/K382 is unlikely to be dependent on p53 phosphorylation at Ser15, Ser20, and Ser392 sites. Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21Waf1/Cip1 expression.
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朱卫国, Zunyan Dai, , Wei-Guo Zhu, Carl D. Morrison, Romulo M. Brena, Dominic J. Smiraglia, Aparna Raval, Yue-Zhong Wu, Laura J. Rush, Patrick Ross, Julian R. Molina, Gregory A. Otterson and Christoph Plass, *
Human Molecular Genetics, 2003, Vol. 12, No.7 791-801,-0001,():
-1年11月30日
Amplification of oncogenes is an important mechanism that can cause gene overexpression and contributes to tumor development. The identification of amplified regions might have both prognostic and therapeutic significance. We used primary lung carcinomas and lung cancer cell lines for restriction landmark genomic scanning (RLGS) to identify novel amplified sequences. Enhanced RLGS fragments that indicate gene amplification were observed in primary tumors and lung cancer cell lines of both non-small cell lung cancer and small cell lung cancer. We identified one novel amplicon on chromosome 11q22, in addition to previously reported amplicons that include oncogenes MYCC, MYCL1 and previously identified amplification of chromosomal regions 6q21 and 3q26-27. Amplification of 11q22 has been reported in other types of cancer and was refined to an 1.19 Mbp region for which the complete sequence is available. Based on a patient sample with a small region of low-level amplification we were able to further narrow this region to 0.92 Mbp. Genes localized in this region include two inhibitors of apoptosis (cIAP1 and cIAP2). Immunohistochemistry and western blot analysis identified cIAP1 and cIAP2 as potential oncogenes in this region as both are overexpressed in multiple lung cancers with or without higher copy numbers.
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