Identification of a GABP Feedback Loop and its Role in Tumor Cell Immortality

GABP 反馈环路的识别及其在肿瘤细胞永生中的作用

基本信息

项目摘要

Project Summary A fundamental hallmark of human cancers is their ability to overcome replicative senescence and achieve cellular immortality. Normally silenced during differentiation in somatic cells, 90% of human tumors reactivate Telomerase Reverse Transcriptase (TERT) expression early during tumorigenesis to achieve cellular immortality. TERT, the catalytic subunit of telomerase, complexes with the RNA template molecule TERC and other proteins and binds to and extends the repetitive sequences at chromosomal ends, known as telomeres. Recently, non-coding mutations in the TERT promoter (TERTp) have been described in many cancers. These TERTp mutations are the most common non-coding mutation across all cancers and are the most frequent mutations in many cancers, such as 83% of IDH wildtype glioblastomas (GBM), the most common and deadly form of adult brain tumors. These mutations result in the formation of canonical E26 Transformation Specific (ETS) binding motifs that work in tandem with TERTp native ETS sites to recruit a specific ETS transcription factor, the GA-binding protein (GABP) complex. Our lab has demonstrated that this recruitment of GABP is necessary for TERT reactivation and maintenance of tumor cell immortality. Furthermore, our lab has shown, through CRISPR-cas9 mediated mutation of the tetramer forming subunit, GABPB1L (B1L), that the tetrameric form of GABP is necessary for this maintenance of tumor cell immortality. Interestingly, while CRISPR-Cas9 mediated ablation of B1L does not show a reduction in TERT expression, it does show a large increase in the GABP dimer specific subunit, GABPB1S (B1S). Importantly, it seems that this increase in B1S expression may be due to a GABP tetramer mediated negative feedback loop. Furthermore, preliminary evidence suggests that this increase in B1S may allow B1S containing dimers to bind to the mutant TERTp and maintain TERT expression. Broadly, this study aims to elucidate the molecular mechanisms underlying the maintenance of TERT expression during states of B1L elimination. In doing so, this study will determine the mechanisms underlying B1S expression upregulation during B1L reduction and will determine if B1S-containing GABP dimers are competent regulators of the mutant TERTp. Telomerase has long been an attractive therapeutic target for the reversal of tumor cell immortality; however, attempts to target telomerase have been mostly unsuccessful due to telomerase expressing stem cells. Prior studies suggest that targeting B1L in TERTp mutant cancers would allow for tumor specific inhibition of telomerase, however, our data have revealed that this approach is more complicated than previously appreciated. Importantly, the findings from these investigations will guide the design and development of effective and durable therapies targeting the GABP-TERT axis for the reversal of tumor cell immortality in TERTp mutant cancers such as glioblastoma, melanoma, bladder cancer, and many others.
项目摘要 人类癌症的一个基本特征是它们克服复制性衰老的能力, 实现细胞永生通常在体细胞分化过程中沉默,90%的人类肿瘤 在肿瘤发生早期重新激活端粒酶逆转录酶(TERT)表达, 细胞永生端粒酶催化亚单位TERT与RNA模板分子复合 TERC和其他蛋白质结合并延伸染色体末端的重复序列,称为TERC。 端粒最近,已经在许多研究中描述了TERT启动子(TERTp)中的非编码突变。 癌的这些TERTp突变是所有癌症中最常见的非编码突变,也是导致癌症发生的主要原因。 许多癌症中最常见的突变,如83%的IDH野生型胶质母细胞瘤(GBM), 一种常见且致命的成人脑瘤这些突变导致典型E26的形成。 转化特异性(ETS)结合基序,其与TERTp天然ETS位点串联工作以募集TERTp特异性结合基序。 特异性ETS转录因子,GA结合蛋白(GABP)复合物。我们的实验室已经证明, GABP的募集对于TERT再活化和维持肿瘤细胞永生是必需的。 此外,我们的实验室已经表明,通过CRISPR-cas9介导的四聚体形成亚基突变, GABPB 1 L(B1 L),GABP的四聚体形式是维持肿瘤细胞永生所必需的。 有趣的是,虽然CRISPR-Cas9介导的B1 L消融没有显示TERT的减少, 表达,它确实显示出GABP二聚体特异性亚基GABPB 1 S(B1 S)的大幅增加。重要的是 似乎B1 S表达的增加可能是由于GABP四聚体介导的负反馈环。 此外,初步证据表明,B1 S的这种增加可能允许含有B1 S的二聚体结合 突变的TERTp并维持TERT表达。概括地说,这项研究的目的是阐明 在B1 L消除状态期间维持TERT表达的潜在机制。在这样做时, 这项研究将确定B1 L减少过程中B1 S表达上调的潜在机制, 确定含B1 S的GABP二聚体是否是突变TERTp的有效调节剂。端粒酶 长期以来一直是逆转肿瘤细胞永生的有吸引力的治疗靶点;然而,靶向 由于端粒酶表达干细胞,端粒酶大多是不成功的。先前的研究表明, 在TERTp突变型癌症中靶向B1 L将允许肿瘤特异性抑制端粒酶,然而,我们的研究发现, 数据显示,这种方法比以前认识到的更复杂。重要的是 这些研究的结果将指导设计和开发有效和持久的治疗方法 靶向GABP-TERT轴,用于逆转TERTp突变型癌症中的肿瘤细胞永生, 胶质母细胞瘤、黑色素瘤、膀胱癌和许多其他癌症。

项目成果

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Nicholas Oliver Stevers其他文献

Nicholas Oliver Stevers的其他文献

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{{ truncateString('Nicholas Oliver Stevers', 18)}}的其他基金

Identification of a GABP Feedback Loop and its Role in Tumor Cell Immortality
GABP 反馈环路的识别及其在肿瘤细胞永生中的作用
  • 批准号:
    10403601
  • 财政年份:
    2020
  • 资助金额:
    $ 4.16万
  • 项目类别:

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