P53 PROTEIN/PROTEIN INTERACTIONS

描述：（改编自研究者摘要）p53肿瘤 抑制蛋白是一种序列特异性转录因子， 在DNA肿瘤病毒转化的细胞中发现。 p53表达于 正常细胞对基因毒性应激的反应，但在癌细胞中， 通常由于基因突变而不活跃。 的分子机制 p53对DNA损伤的反应尚未被破译。 众所周知的是 基因毒性应激导致p53蛋白水平升高，而无任何影响 p53 mRNA水平的变化，以及p53对特异性DNA损伤的反应， 电离辐射等物质需要突变的ATM基因 共济失调毛细血管扩张症（AT）患者。 在初步结果中， P.I.为p53和14-3.3之间的新型相互作用提供了证据。 14-3-3与p53的结合是由电离辐射诱导的，依赖于一种 野生型ATM基因，并增强p53对序列特异性 DNA. 这些发现导致申请人假设， p53对遗传毒性应激反应的ATM依赖性分子机制 涉及14-3-3蛋白质。 为了验证这一假设，他们将： p53/14-3-3相互作用的结构-功能分析 检查 p53/14-3-3互作在组织培养中的生理意义 细胞 研究p53-14-3-3相互作用的生理意义 在体内使用纯合基因靶向小鼠。 这些实验将 建立观察到的相互作用的生理意义， p53和14-3-3，并将促进对法规的理解 p53基因的功能受到DNA损伤 私家侦探的长期目标是作出贡献 本发明涉及阐明p53活性被抑制的分子机制， 导致DNA损伤。 这些研究的意义在于 p53在癌症患者对癌症的反应中起着关键作用， 由于目前的癌症治疗主要利用DNA损伤剂， 以放射或化疗的形式。

DESCRIPTION: (adapted from the investigator's abstract) The p53 tumor suppressor protein is a sequence-specific transcription factor originally discovered in cells transformed by DNA tumor viruses. p53 is expressed in normal cells in response to genotoxic stress, but in cancer cells p53 is often inactive due to genetic mutations. The molecular mechanism by which p53 responds to DNA damage has not been deciphered. What is known is that genotoxic stress leads to increased levels of p53 protein without any effect on p53 mRNA levels and that the response of p53 to specific DNA damaging agents, such as ionizing radiation, requires ATM, the gene that is mutated in patients with ataxia telangiectasia (AT). In Preliminary Results the P.I. provides evidence for a novel interaction between p53 and 14-3.3. Binding of 14-3-3 to p53 is induced by ionizing radiation, is dependent on a wild-type ATM gene and enhances the affinity of p53 for sequence-specific DNA. These findings lead the applicant to the hypothesis that the ATM-dependent molecular mechanism by which p53 responds to genotoxic stress involves 14-3-3 proteins. To test this hypothesis they will: Perform a Structure-Function Analysis of the p53/14-3-3 Interaction. Examine the Physiological Significance of the p53/14-3-3 Interaction in Tissue Culture Cells. Examine the Physiological Significance of the p53-14-3-3 Interaction in Vivo using Homozygous Gene-Targeted Mice. These experiments will establish the physiological significance of the observed interaction between p53 and 14-3-3 and will promote the understanding regarding the regulation of p53 function by DNA damage. The P.I. s long-term goal is to contribute to the elucidation of the molecular mechanism(s) by which p53 activity is induced following DNA damage. The significance of these studies relates to the critical role that p53 has for the response of cancer patients to therapy, since current cancer therapy utilizes primarily DNA damaging agents in the form of radiation or chemotherapeutics.