Delineating ARF negative regulation of PAF1C-dependent oncogenic programs

描绘 ARF 对 PAF1C 依赖性致癌程序的负调控

基本信息

  • 批准号:
    10437541
  • 负责人:
  • 金额:
    $ 8.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-08 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Tumor suppressors (TS) tune the balance of cell growth and death by acting at multiple levels. Deregulation of any of these hierarchies can promote tumorigenesis, impact cancer patient’s survival and response to currently available treatments. Therefore, having a better understanding of these processes and the identification of novel therapeutic targets upon TS loss is a priority in the field of cancer biology. Decades of work have defined how the p14ARF (Alternative Reading Frame) TS operates in a p53-dependent manner to prevent tumorigenesis. However, ARF also operates in a p53-independent manner to potentially “back-up p53”, but the mechanisms remain poorly understood. There is a regained idea in the field to delve into tumor suppressive mechanisms and to leverage the basic biology to therapeutic opportunities. In this context, the major goal of this research proposal is to define how ARF (reactivated upon p53 loss) functions to restrain tumor promoter programs. Our unpublished studies have defined a previously overlooked mechanism of ARF tumor suppression. First, upon p53 loss, reactivated ARF selectively targets the Polymerase Associated Factor 1 complex (PAF1C) at genes encoding the pro-growth GDF and BMP ligands to restrain abnormal cell growth. Second, loss of ARF in primary p53-/- cells de-repress GDF/BMP programs leading to SMAD1/5 phosphorylation and target gene activation (“oncogenic GDF/SMAD axis”), suggesting oncogenic vulnerabilities accrued upon double TS (p53 and ARF) loss emerge as alternative therapeutic targets. However, it remains unknown how ARF inactivates PAF1C in a gene-specific manner and whether the oncogenic GDF/SMAD axis has any diagnostic and therapeutic value. This small grant proposal aims at addressing how ARF inactivates PAF1C in a gene-specific manner to restrain tumor promoter programs and to evaluate the therapeutic value of targeting the oncogenic GDF/SMAD program. Work in this proposal is guided by these previous findings and critical gaps in knowledge to test the central hypothesis that ARF binds Paf1 and the gene-specific factor RUNX1 to block PAF1C assembly in a gene-specific manner thereby restraining tumor promoter programs. To test the underlying hypothesis, we will leverage biochemical and genetic approaches as well as clinically and molecularly annotated preclinical models. Specifically, we will first investigate how ARF binds Paf1 and RUNX1 to block PAF1C assembly in a gene-specific manner (Aim 1), and then probe if tumors bearing double TS (p53 and ARF) loss exhibit reactivation of the oncogenic GDF/SMAD axis and examine its therapeutic and diagnostic potential (Aim 2). Together, elucidating the mechanisms by which ARF negatively regulates PAF1C-dependent tumor promoter transcriptional programs will improve our understanding of an important biological process and offer alternative opportunities to target TS loss in cancers with dual ARF and p53 inactivation (such as sarcoma, pancreas, and lung adenocarcinoma), which is in-line with NCI’s mission to identify novel targets to move the discoveries from the bench to the clinics.
项目总结

项目成果

期刊论文数量(0)
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Ivan D'Orso其他文献

Ivan D'Orso的其他文献

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{{ truncateString('Ivan D'Orso', 18)}}的其他基金

A chemical genetics approach for studies of HIV-1 latency
研究 HIV-1 潜伏期的化学遗传学方法
  • 批准号:
    10711683
  • 财政年份:
    2023
  • 资助金额:
    $ 8.2万
  • 项目类别:
Delineating the Role of KAP1 in WNT-induced Colorectal Cancer
描述 KAP1 在 WNT 诱导的结直肠癌中的作用
  • 批准号:
    10544512
  • 财政年份:
    2022
  • 资助金额:
    $ 8.2万
  • 项目类别:
Delineating the Role of KAP1 in WNT-induced Colorectal Cancer
描述 KAP1 在 WNT 诱导的结直肠癌中的作用
  • 批准号:
    10358964
  • 财政年份:
    2022
  • 资助金额:
    $ 8.2万
  • 项目类别:
Delineating ARF negative regulation of PAF1C-dependent oncogenic programs
描绘 ARF 对 PAF1C 依赖性致癌程序的负调控
  • 批准号:
    10588156
  • 财政年份:
    2022
  • 资助金额:
    $ 8.2万
  • 项目类别:
Exploring the mechanism of ADAP1 control of HIV latency and reactivation in CD4 T cells
探索 ADAP1 控制 CD4 T 细胞中 HIV 潜伏期和再激活的机制
  • 批准号:
    10176412
  • 财政年份:
    2020
  • 资助金额:
    $ 8.2万
  • 项目类别:
Exploring the mechanism of ADAP1 control of HIV latency and reactivation in CD4 T cells
探索 ADAP1 控制 CD4 T 细胞中 HIV 潜伏期和再激活的机制
  • 批准号:
    10082399
  • 财政年份:
    2020
  • 资助金额:
    $ 8.2万
  • 项目类别:
Novel small molecules to reactivate latent HIV and sensitize to anti-viral therapies
新型小分子可重新激活潜伏的艾滋病毒并使抗病毒疗法敏感
  • 批准号:
    9535050
  • 财政年份:
    2016
  • 资助金额:
    $ 8.2万
  • 项目类别:
Novel small molecules to reactivate latent HIV and sensitize to anti-viral therapies
新型小分子可重新激活潜伏的艾滋病毒并使抗病毒疗法敏感
  • 批准号:
    9291553
  • 财政年份:
    2016
  • 资助金额:
    $ 8.2万
  • 项目类别:
Transcriptional regulatory mechanisms shaping HIV proviral fate
影响HIV原病毒命运的转录调控机制
  • 批准号:
    10322694
  • 财政年份:
    2015
  • 资助金额:
    $ 8.2万
  • 项目类别:
Transcriptional regulatory mechanisms shaping HIV proviral fate
影响HIV原病毒命运的转录调控机制
  • 批准号:
    9926935
  • 财政年份:
    2015
  • 资助金额:
    $ 8.2万
  • 项目类别:

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