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Development and characterization of a humanp53 transgenic mouse model.

机译：人类p53转基因小鼠模型的开发和表征。

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摘要

Fifty years of cancer research has provided us with many clues on the development of cancer. We know the body has various natural defense mechanisms to prevent cancer, an extremely important one being the expression of the a tumor suppressor protein, p53. Approximately half of all tumors have lost p53 activity through mutation or deletion while the other half display a dysfunction in the p53 pathway. Functions of p53 are believed to include the activation of transcription of pro-apoptosic and cell cycle arrest genes causing apoptosis or G1 arrest once p53 is activated. p53-null mice develop spontaneous tumors between the ages of 3-6 months, and p53-null cells have a variety of abnormalities including defects in apoptosis, G1 arrest, and centrosome duplication. The cause of spontaneous tumorigenesis in p53-null mice is still unknown. To understand the complexity of p53 activation, a transgenic mouse strain, carrying a TP53 transgene backcrossed into the mouse p53-null background (named SWAP), was generated. Human p53 is up regulated after y-irradiation and UV-irradiation in SWAP cells and is phosphorylated normally by murine kinases responsible for activation of p53 after stress. However, human p53 did not protect against induced carcinogenesis after either genotoxic or oncogenic stress, comparable in phenotype to p53-null mice. Loss of human p53 activity after stress was found through immunoprecipitation and treatment with nutlin-3a to be due to an increase in Mdm2 binding. While dissociation of Mdm2 gave rise to partial human transgenic p53 activity, loss of Mdm4 by siRNA treatment, in addition to inhibition of Mdm2 binding, fully activated p53. Surprisingly, human p53 delays the mice from spontaneous tumorigenesis, possibly due to normal regulation of transrepression, G2 arrest, and/or centrosome duplication. This suggests a novel role for p53 in the prevention of spontaneous tumorigenesis that is distinct from its role in protection from genotoxic or oncogenic stress. Therefore, characterization of SWAP mice would lead to the understanding of how p53 inhibits spontaneous tumorigenesis under normal conditions. Consequently, the p53 function needed to prevent spontaneous tumorigenesis may be revealed.
机译：五十年来的癌症研究为我们提供了有关癌症发展的许多线索。我们知道人体具有多种预防癌症的天然防御机制，其中极为重要的一种就是抑癌蛋白p53的表达。所有肿瘤中约有一半因突变或缺失而失去了p53活性，而另一半则在p53途径中出现功能障碍。据信p53的功能包括激活促凋亡和细胞周期阻滞基因的转录，一旦激活p53，就会导致细胞凋亡或G1阻滞。 p53缺失的小鼠在3至6个月大时会自发形成肿瘤，p53缺失的细胞具有多种异常，包括凋亡缺陷，G1阻滞和中心体复制。 p53无效小鼠中自发肿瘤发生的原因仍然未知。为了了解p53激活的复杂性，生成了带有TP53转基因回交进入小鼠p53-null背景（称为SWAP）的转基因小鼠品系。人p53在SWAP细胞中受到y辐射和UV辐射后被上调，并且在应激后通常被负责激活p53的鼠激酶磷酸化。然而，人类p53在遗传毒性或致癌性应激后均不能预防诱导的癌变，其表型与p53无效小鼠相似。通过免疫沉淀和用nutlin-3a处理发现应激后人p53活性的丧失是由于Mdm2结合的增加。尽管Mdm2的解离会导致部分人类转基因p53活性，但通过抑制siRNA处理，Msi4通过siRNA丢失Mdm4会完全激活p53。出人意料的是，人p53可能延迟了小鼠的自发肿瘤发生，这可能是由于正常的反式调控，G2阻滞和/或中心体复制。这表明p53在预防自发性肿瘤发生中的新作用与其在保护基因毒性或致癌性应激中的作用不同。因此，SWAP小鼠的表征将导致人们理解p53在正常条件下如何抑制自发性肿瘤发生。因此，可以揭示预防自发肿瘤发生所需的p53功能。

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  • 作者

    Dudgeon, Crissy.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 193 p.
  • 总页数 193
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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