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首页> 外文学位 >Control ofp63 protein stability and prolyl isomerase Pin1-mediated regulation of retinoblastoma protein.
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Control ofp63 protein stability and prolyl isomerase Pin1-mediated regulation of retinoblastoma protein.

机译：p63蛋白稳定性控制和脯氨酰异构酶Pin1介导的视网膜母细胞瘤蛋白调节。

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摘要

This thesis investigated novel regulation of two cell cycle regulators, p53-related p63 and retinoblastoma protein (Rb).; The p63 gene encodes six isoforms. The TAp63 isoforms possess a N-terminal domain capable of transactivating a set of genes including some p53 downstream targets. Accumulating evidence indicates that TAp63 plays an important role in the regulation of cell proliferation, differentiation and apoptosis. The DeltaNp63 isoforms lack the N-terminal transactivation domain and function to inhibit p63 and other p53 family members. Mutations in the p63 gene have been linked to human diseases including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndromes. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndromes are transcriptionally inert and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activity and that p63 is degraded in a proteasome-dependent, murine double minute-2 (MDM2)-independent pathway. In addition, the N-terminal transactivation domain of p63 is critical for its protein degradation. Furthermore, the wild type TAp63gamma acts in trans to promote degradation of mutant TAp63gamma defective in DNA-binding. Moreover, DeltaTAp63gamma inhibits transactivation activity of TAp63 and stabilizes TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.; The tumor suppressor retinoblastoma protein is frequently inactivated in a variety of human cancers. While Rb plays a pivotal role in cell cycle G1-S transition, emerging evidence indicates that Rb is also critical for S-phase checkpoint control in cellular response to DNA damage. Here we show that CDK-mediated phosphorylation of Rb facilitates its interaction with Pin1, a phosphorylation-specific peptidyl-prolyl isomerase. Pin1 inhibits protein phosphatase 2A (PP2A)-mediated Rb dephosphorylation in vitro , attenuates Rb dephosphorylation upon S-phase DNA damage, and compromises the gamma-irradiation induced S-phase checkpoint control. Ablation of Pin1 leads to a significant increase in hypophosphorylated Rb, accelerated Rb dephosphorylation and increased cell growth arrest upon S-phase DNA damage. Furthermore, Pin1 inhibits Rb dephosphorylation at mitotic exit. Moreover, Pin1 is overexpressed, concomitant with hyperphosphorylated Rb in human breast cancers. Together, these data reveal a novel regulatory pathway for Rb in which Pin1 is critical for modulation of Rb function in S-phase checkpoint control upon DNA damage.
机译：本论文研究了两种细胞周期调节子，p53相关的p63和成视网膜细胞瘤蛋白（Rb）的新调控。 p63基因编码六个同工型。 TAp63同工型具有一个N端结构域，该结构域能够反式激活一组基因，包括一些p53下游靶标。越来越多的证据表明，TAp63在调节细胞增殖，分化和凋亡中起着重要作用。 DeltaNp63亚型缺乏N末端反式激活结构域，并具有抑制p63和其他p53家族成员的功能。 p63基因的突变与人类疾病有关，包括外胚层外胚层发育不良和面部c裂（EEC）综合征。在这项研究中，我们表明在EEC综合征中发现的具有单个氨基酸取代的突变p63蛋白在转录上是惰性的，并且高度稳定。我们证明，TAp63蛋白的表达受其特定的DNA结合和反式激活活动的严格控制，并且p63在蛋白酶体依赖性，鼠类doubleminute-2（MDM2）独立途径中被降解。此外，p63的N末端反式激活结构域对其蛋白质降解至关重要。此外，野生型TAp63gamma反式起作用以促进DNA结合缺陷的突变型TAp63gamma的降解。此外，DeltaTAp63gamma抑制TAp63的反式激活活性并稳定TAp63蛋白。综上所述，这些数据表明了一个类似于p53-MDM2反馈回路的p63调节反馈回路。肿瘤抑制性视网膜母细胞瘤蛋白经常在多种人类癌症中失活。尽管Rb在细胞周期G1-S过渡中起着关键作用，但新兴证据表明Rb对于细胞对DNA损伤的反应中S期检查点控制也至关重要。在这里，我们显示CDK介导的Rb磷酸化促进其与Pin1（磷酸化特异性肽基脯氨酰异构酶）的相互作用。 Pin1在体外抑制蛋白磷酸酶2A（PP2A）介导的Rb去磷酸化，在S期DNA损伤后减弱Rb去磷酸化，并损害了γ射线诱导的S期检查点控制。 Pin1的消融会导致次磷酸化Rb的显着增加，Rb脱磷酸化的加速和S期DNA损伤后细胞生长停滞的增加。此外，Pin1抑制有丝分裂出口处的Rb去磷酸化。而且，Pin1在人类乳腺癌中过表达，并伴有高磷酸化Rb。总之，这些数据揭示了Rb的新型调节途径，其中Pin1对于DNA损伤时S期检查点控制中Rb功能的调节至关重要。

著录项

  • 作者

    Ying, Haoqiang.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Molecular.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;生物化学;
  • 关键词

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