Function of p53 and its target genes
p53及其靶基因的功能
基本信息
- 批准号:12213115
- 负责人:
- 金额:$ 42.82万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research on Priority Areas
- 财政年份:2000
- 资助国家:日本
- 起止时间:2000 至 2004
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
1. Novel p53-target genes : Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. To identify novel p53-inducible genes, we compared the expression of genes in normal mouse embryo fibroblasts to p53-null cells by cDNA representational difference analysis (RDA). We have identified that expression of endogenous SCN3B (sodium channel subunit beta 3) and OPN (osteopontin) are upregulated in mouse embryonic fibroblasts by DNA damage in a p53-dependent manner. The p53-directed regulation of OPN expression suggests a novel model of p53 participation in immunosurveillance, involving interaction with the host immune system to prevent damaged cells from undergoing malignant transformation. The results presented above also suggest that SCN3B mediates a p53-dependent apoptotic pathway and may be a candidate for gene therapy combined with anticancer drugs.2. Biological functions of the p53 family member genes : p63 and p73 were re … More cently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. To determine how p63 and p73 are involved in carcinogenesis and normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not p53. We identified the JAG1 and JAG2 genes, encoding ligands for the Notch receptors, and the PEDF gene are direct target of p63 and p73. We also found that IL4 receptor alpha is upregulated by p73. These findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development. Our data also suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.3. Adenovirus-mediated transfer of the p53 family genes, p73 and p63 induces cell cycle arrest and apoptosis in human cancer cell lines : p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p63, in cancer gene therapy, we introduced p53, p73 and p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p63gamma ; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p63gamma. Transduction of p73beta and p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy. Less
1.新型p53靶基因:肿瘤抑制基因p53是一种转录因子,在细胞应激时诱导生长停滞和/或凋亡。为了鉴定新的p53诱导基因,我们通过cDNA代表性差异分析(RDA)比较了正常小鼠胚胎成纤维细胞和p53缺失细胞中基因的表达。我们已经确定,内源性SCN 3B(钠通道β 3亚基)和骨桥蛋白(骨桥蛋白)的表达上调小鼠胚胎成纤维细胞的DNA损伤中的p53依赖性的方式。p53介导的骨桥蛋白表达调控提示了p53参与免疫监视的一种新模式,涉及与宿主免疫系统的相互作用,以防止受损细胞发生恶性转化。上述结果还表明,SCN 3B介导p53依赖性凋亡途径,可能成为基因治疗联合抗癌药物的候选者. p53家族成员基因p63和p73的生物学功能与p53家族成员基因p63和p73的生物学功能密切相关。 ...更多信息 目前被鉴定为p53基因家族的成员。然而,与p53相反,p63和p73在人类癌症中很少突变。为了确定p63和p73是如何参与癌发生和正常发育的,我们试图鉴定由p63和/或p73而不是p53特异性调控的靶基因。我们鉴定了编码Notch受体配体的JAG1和JAG2基因,以及PEDF基因是p63和p73的直接靶点。我们还发现IL 4受体α被p73上调。这些发现显示了p53家族基因和Notch信号之间的关联,并提出了p53家族基因参与正常发育的潜在分子机制。我们的数据还表明IL-4R α可以部分介导某些免疫应答和p73依赖性细胞死亡。腺病毒介导的p53家族基因、p73和p63的转移诱导人类癌细胞系中的细胞周期停滞和凋亡:p53基因疗法正在临床上测试用于治疗人类癌症,然而,一些癌症模型(体内和体外)对p53具有抗性。为了探讨p53同源基因p73和p63在肿瘤基因治疗中的潜在应用,我们通过腺病毒载体将p53、p73和p63导入大肠癌细胞系,并比较它们对细胞生长的影响。在测试的10个细胞系中,6个细胞系在p53、p73 β或p63 γ转导后显示出类似的反应; 2个细胞系经历细胞周期停滞,3个细胞系表现出凋亡,1个细胞系在转导后显示无作用。对细胞周期进程的影响在其他四种细胞系中是可变的。有趣的是,三个细胞系对p53介导的凋亡有抗性,包括两个具有内源性野生型p53等位基因的细胞系,但在p73 β或p63 γ转导后发生凋亡。p73 β和p63 γ的转导也降低了体内两种结直肠癌细胞的致瘤性。这些结果表明,腺病毒介导的p73 β和p63 γ转移是治疗人类癌症,特别是对p53基因治疗耐药的肿瘤的潜在新方法。少
项目成果
期刊论文数量(124)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer
- DOI:10.1038/sj.gt.3301538
- 发表时间:2001-09
- 期刊:
- 影响因子:5.1
- 作者:Y. Sasaki;I. Morimoto;S. Ishida;T. Yamashita;K. Imai;T. Tokino
- 通讯作者:Y. Sasaki;I. Morimoto;S. Ishida;T. Yamashita;K. Imai;T. Tokino
Toyota, M., et al.: "Epigenetic inactivation of CHFR in human tumors."Proc.Natl.Acad.Sci.USA. 100・13. 7818-7823 (2003)
Toyota, M., et al.:“人类肿瘤中 CHFR 的表观遗传失活”。Proc.Natl.Acad.Sci.USA 100・13 (2003)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA)
- DOI:10.1002/glia.10343
- 发表时间:2004-03-15
- 期刊:
- 影响因子:6.2
- 作者:Takamura, Y;Ikeda, H;Sato, N
- 通讯作者:Sato, N
Identification of SCN3B as a novel p53-inducible proapoptotic gene
- DOI:10.1038/sj.onc.1208067
- 发表时间:2004-10-14
- 期刊:
- 影响因子:8
- 作者:Adachi, K;Toyota, M;Tokino, T
- 通讯作者:Tokino, T
Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-g-induced HLA-DR expression in colorectal and gastric cancer cells.
II 类反式激活因子 (CIITA) 的表观遗传失活与结直肠癌细胞和胃癌细胞中干扰素 g 诱导的 HLA-DR 表达缺失有关。
- DOI:
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:Ueda;G.;Satoh A
- 通讯作者:Satoh A
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TOKINO Takashi其他文献
TOKINO Takashi的其他文献
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{{ truncateString('TOKINO Takashi', 18)}}的其他基金
A better understanding of p53 network for cancer therapy
更好地了解用于癌症治疗的 p53 网络
- 批准号:
16K07122 - 财政年份:2016
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
New insights into p53 signaling regulation to cure cancer
p53 信号传导调控治疗癌症的新见解
- 批准号:
25430115 - 财政年份:2013
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
High-throughput screening for peptides that inhibit the interaction or MDM4 with p53
高通量筛选抑制 MDM4 与 p53 相互作用的肽
- 批准号:
23659658 - 财政年份:2011
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Functional analysis of CHFR: Diagnostic and therapeutic application for oral squamous cell cancer
CHFR 的功能分析:口腔鳞状细胞癌的诊断和治疗应用
- 批准号:
20390519 - 财政年份:2008
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Diagnostic and therapeutic application of cell-cycle checkpoint genes for oral squamous cell cancer.
细胞周期检查点基因在口腔鳞状细胞癌的诊断和治疗中的应用。
- 批准号:
18390545 - 财政年份:2006
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
p53 family : function and cancer therapy
p53 家族:功能和癌症治疗
- 批准号:
17013072 - 财政年份:2005
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Diagnostic and therapeutic application of checkpoint gene CHFR in oral squamous cell cancer.
检查点基因CHFR在口腔鳞状细胞癌诊断和治疗中的应用。
- 批准号:
16390597 - 财政年份:2004
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Functional analysis of p53-target genes.
p53 靶基因的功能分析。
- 批准号:
11138246 - 财政年份:1999
- 资助金额:
$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas (A)
相似海外基金
Protein phosphorylation of tumor suppressor gene p53 in leukemia cells and regulation of apoptosis-rated gene expression
白血病细胞中抑癌基因p53的蛋白磷酸化及凋亡相关基因表达的调控
- 批准号:
10670944 - 财政年份:1998
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$ 42.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
MUTATIONAL AND FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR GENE
P53 肿瘤抑制基因的突变和功能分析
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5201596 - 财政年份:
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$ 42.82万 - 项目类别:
Genetic Susceptibility to Loss of Tumor Suppressor Gene Function
肿瘤抑制基因功能丧失的遗传易感性
- 批准号:
7967960 - 财政年份:
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$ 42.82万 - 项目类别:
MUTATIONAL AND FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR GENE
P53 肿瘤抑制基因的突变和功能分析
- 批准号:
2463704 - 财政年份:
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MUTATIONAL AND FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR GENE
P53 肿瘤抑制基因的突变和功能分析
- 批准号:
6100879 - 财政年份:
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Mutational and Functional Analysis of the p53 Tumor Suppressor Gene
p53抑癌基因的突变和功能分析
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肿瘤抑制基因功能丧失的遗传易感性
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MUTATIONAL AND FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR GENE
P53 肿瘤抑制基因的突变和功能分析
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6160979 - 财政年份:
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MUTATIONAL AND FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR GENE
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