Molecular Studies on Transactivation Potential of PAX9

PAX9 反式激活潜力的分子研究

基本信息

  • 批准号:
    7015586
  • 负责人:
  • 金额:
    $ 4.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-02-15 至 2006-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Pax9 is a member of the Pax family that consists of nine genes encoding nuclear transcription factors that play key roles in patterning and embryogenesis. In recent years, mouse and human genetic studies have provided definitive evidence of a key role for Pax9 in the patterning of dentition. Functional deletion of the Pax9 gene also results in an arrest in tooth development in mice. Recent studies on humans have associated mutations in PAX9, with autosomal dominantly inherited forms of tooth agenesis that primarily affects posterior teeth. Of the 11 PAX9 mutations reported thus far, 6 occur in the region of the paired domain that is encoded by exon 2 of PAX9. The latter is important in mediating the DNA-binding activities of PAX9. Apart from DNA-binding properties, however, relatively little is known about the role of Pax9 as a transcriptional regulator. Studies on other Pax family members point to the COOH terminal region that is characteristically rich in proline, serine and threonine as potentially mediating transactivation functions in vivo. We recently identified a novel frameshift mutation (793InsC) in the COOH-terminal domain (exon 4) of PAX9 in members of a large family with congenitally missing posterior teeth. Understanding the role of exon 4 will hence shed valuable insights into the molecular mechanisms underlying PAX9 functions during normal and abnormal tooth development. Two specific aims are proposed to test the fundamental hypothesis that the region of the COOH terminal that encompasses amino acid 264 (nt793) is critical for the transactivation function(s) of PAX9 and mutations in this region inactivate the transactivation domain and compromise PAX9-mediated transactivation of target genes during tooth morphogenesis. Aim 1 will delineate the transactivation function of Pax9 by identifying the minimal region of the COOH-terminal that yields maximal luciferase reporter-gene activity in cellular co-transfection assays. Aim 2 will evaluate the consequences of the 793InsC/amino acid 264 mutation on Pax9 transactivation and its protein structure. The role of the 793InsC/amino acid 264 Pax9 mutation will be investigated by determining alterations in transactivation of the 793InsC mutant protein relative to the wild-type. To complement the biochemical characterization of the differences in transactivation, circular dichroism will be utilized to investigate structural alteration in the COOH-terminal transactivation domain resulting from the 793InsC/amino acid 264 Pax9 mutation. Knowledge of the mechanism by which Pax9 transactivate target genes will facilitate a better understanding of the etiologic significance of mutations in PAX9 as well as provide insights into the regulation of transcription in eukaryotic cells. Understanding the biochemical function of Pax9 will ultimately provide a unique tool for the study of the genetic and molecular control of tooth morphogenesis.
描述(由申请人提供):Pax 9是Pax家族的成员,该家族由编码在图案形成和胚胎发生中起关键作用的核转录因子的9个基因组成。近年来,小鼠和人类的遗传学研究提供了明确的证据,表明Pax 9在牙列形成中起着关键作用。Pax 9基因的功能性缺失也导致小鼠牙齿发育停滞。最近对人类的研究将PAX 9的突变与常染色体显性遗传形式的牙齿发育不全(主要影响后牙)相关联。在迄今为止报道的11种PAX 9突变中,6种发生在PAX 9外显子2编码的配对结构域区域。后者在介导PAX 9的DNA结合活性中是重要的。然而,除了DNA结合特性之外,对Pax 9作为转录调节因子的作用知之甚少。对其他Pax家族成员的研究指出,COOH末端区域富含脯氨酸、丝氨酸和苏氨酸,可能在体内介导反式激活功能。我们最近发现了一个新的移码突变(793 InsC)的COOH-末端结构域(外显子4)的PAX 9在一个大家庭的成员先天性缺失后牙。因此,了解外显子4的作用将有助于深入了解PAX 9在正常和异常牙齿发育过程中的分子机制。提出了两个具体的目标来测试的基本假设,COOH末端的区域,包括氨基酸264(nt 793)是至关重要的PAX 9的反式激活功能(S)和突变,在该区域的反式激活结构域和妥协PAX 9介导的反式激活的目标基因在牙齿形态发生。目的1将描绘Pax 9的反式激活功能,通过确定COOH-末端的最小区域,在细胞共转染试验中产生最大的荧光素酶抑制剂基因活性。目的2:研究793 InsC/氨基酸264突变对Pax 9反式激活及其蛋白结构的影响。将通过确定793 InsC突变蛋白相对于野生型的反式激活改变来研究793 InsC/氨基酸264 Pax 9突变的作用。为了补充反式激活差异的生物化学表征,将利用圆二色性来研究由793 InsC/氨基酸264 Pax 9突变引起的COOH末端反式激活结构域的结构改变。了解Pax 9反式激活靶基因的机制将有助于更好地理解PAX 9突变的病因学意义,并为真核细胞转录调控提供见解。了解Pax 9的生物化学功能将最终为研究牙齿形态发生的遗传和分子控制提供一个独特的工具。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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HITESH KAPADIA其他文献

HITESH KAPADIA的其他文献

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{{ truncateString('HITESH KAPADIA', 18)}}的其他基金

Molecular Studies on Transactivation Potential of PAX9
PAX9 反式激活潜力的分子研究
  • 批准号:
    6853289
  • 财政年份:
    2005
  • 资助金额:
    $ 4.95万
  • 项目类别:
Molecular Studies on Transactivation Potential of PAX9
PAX9 反式激活潜力的分子研究
  • 批准号:
    7281045
  • 财政年份:
    2005
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6369007
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6744052
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6516684
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    7287103
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6909098
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6634720
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
Cellular and Molecular Determinants of Tooth Eruption
牙齿萌出的细胞和分子决定因素
  • 批准号:
    6903840
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:

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