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首页> 外文学位 >Cloning of a novel phosphoinositide binding protein PIPHD34 and functional analysis of LKB1, the tumor suppressor found in Peutz -Jegher's syndrome.
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Cloning of a novel phosphoinositide binding protein PIPHD34 and functional analysis of LKB1, the tumor suppressor found in Peutz -Jegher's syndrome.

机译：新型磷酸肌醇结合蛋白PIPHD34的克隆和LKB1的功能分析，LKB1是在Peutz-Jegher综合征中发现的抑癌基因。

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摘要

This thesis is made up of two main parts. The first is the identification of a potential anti-apoptotic protein that is a novel phosphoinositide binding protein. The second part is the study of a pro-apoptotic tumor suppressor kinase.;A murine PHD zinc finger-containing protein, designated PIPHD34 ( phosphatidylinositol-binding, PHD domain-containing protein of 34 kDa), by small pool expression cloning using polyphosphate-based affinity resin. The predicted amino acid sequence of PIPHD34 is orthologous to human ING1L. Recombinant full length PIPHD34 or its PHD domain alone interacts with phosphatidylinositol 3,4,5-trisphosphate in vitro. We show here that PtdIns 3-kinase activity recruits PIPHD34 into nuclear speckles and regulates its ability to upregulate p21 WAF1/CIP1 expression. We conclude that phosphatidylinositol 3,4,5-trisphosphate may be an endogenous ligand of PIPHD34 and regulates its function in the nucleus. This gene may play a role in mediating resistance to apoptosis in cancers.;Apoptosis is an important mechanism for regulation of cell numbers. Dysregulation of apoptosis is a key step in tumorigenesis. Here we investigate the mechanism and function of the LKB1 gene product responsible for the Peutz-Jegher syndrome (PJS), a rare hereditary disease characterized by a predisposition to develop benign and malignant tumors of many tissue origins. The LKB1 gene encodes a widely expressed serine/threonine kinase. We demonstrate here that LKB1 is a novel pro-apoptotic protein that mediates cell death in a p53-dependent manner. p53 physically interacts with LKB1 and the interaction is enhanced during apoptosis. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. Expression of a dominant negative LKB1 mutant inhibits a subset of p53-dependent apoptotic pathways. In vivo, LKB1 is highly up-regulated in pyknotic intestinal epithelial cells. In contrast, the small intestine of Peutz-Jegher patients shows mosaic expression of LKB1, with most of the small bowel polyps devoid of LKB1 staining. This is accompanied by a concomitant dramatic reduction of physiologic apoptosis in the polyps. We propose that the loss of apoptosis in Peutz-Jeghers syndrome is a key factor responsible for the formation of multiple benign intestinal polyps in PJS and possibly for the development of malignant tumors as well.;Both these studies new survival and apoptotic pathways that may be important in cancer cells. They also highlight p53-dependent and p53-independent events in cells. Furthermore they demonstrate the functional interplay between the phosphoinositide 3-kinase pathway, the p53 tumor suppressor gene and the mitochondrion in survival and cell death.
机译：本论文由两个主要部分组成。第一个是鉴定潜在的抗凋亡蛋白，它是一种新型的磷酸肌醇结合蛋白。第二部分是对促凋亡肿瘤抑制激酶的研究。通过使用多磷酸盐-磷酸酶的小池表达克隆，将鼠PHD含锌指蛋白称为PIPHD34（磷脂酰肌醇结合蛋白，含PHD域的蛋白为34 kDa）。基亲和树脂。 PIPHD34的预测氨基酸序列与人ING1L同源。重组全长PIPHD34或其单独的PHD结构域在体外与磷脂酰肌醇3,4,5-三磷酸酯相互作用。我们在这里显示PtdIns 3激酶活性将PIPHD34募集到核斑点中，并调节其上调p21 WAF1 / CIP1表达的能力。我们得出结论，磷脂酰肌醇3,4,5-三磷酸可能是PIPHD34的内​​源性配体，并调节其在细胞核中的功能。该基因可能在介导癌症的凋亡抗性中发挥作用。凋亡是调节细胞数量的重要机制。细胞凋亡的失调是肿瘤发生中的关键步骤。在这里，我们调查了负责Peutz-Jegher综合征（PJS）的LKB1基因产物的机制和功能，该综合征是一种罕见的遗传性疾病，其特征是易患多种组织起源的良性和恶性肿瘤。 LKB1基因编码广泛表达的丝氨酸/苏氨酸激酶。我们在这里证明，LKB1是一种新型的促凋亡蛋白，以p53依赖性的方式介导细胞死亡。 p53与LKB1发生物理相互作用，并且在凋亡过程中增强了相互作用。 LKB1蛋白存在于活细胞的细胞质和细胞核中，并且在凋亡过程中易位至线粒体。显性负性LKB1突变体的表达抑制p53依赖的凋亡途径的子集。在体内，LKB1在结直肠肠道上皮细胞中高度上调。相反，Peutz-Jegher患者的小肠显示LKB1的镶嵌表达，而大多数小肠息肉没有LKB1染色。这伴随着息肉中生理性细胞凋亡的显着减少。我们认为Peutz-Jeghers综合征的细胞凋亡丧失是导致PJS多发性良性肠息肉形成并可能导致恶性肿瘤发展的关键因素;这两方面的研究都可能是新的生存和凋亡途径。在癌细胞中很重要。他们还强调了细胞中p53依赖性和p53依赖性事件。此外，他们证明了磷酸肌醇3激酶途径，p53抑癌基因和线粒体在存活和细胞死亡中的功能相互作用。

著录项

  • 作者

    Karuman, Philip M.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 188 p.
  • 总页数 188
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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