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
- 来源:
- 关键词:Abnormal CellAcuteAddressAffectApplications GrantsBackBindingBiochemicalBiochemical GeneticsBiological ProcessBiologyCDKN2A geneCancer BiologyCancer PatientCancer cell lineCell DeathCell LineCellsClinicClinicalComplexDataDevelopmentDiagnosticDifferentiation and GrowthEquilibriumExhibitsGDF15 geneGene ActivationGene Expression RegulationGenesGenetic TranscriptionGoalsGrowthHumanIn VitroInterruptionKnowledgeLigandsLung AdenocarcinomaMaintenanceMalignant NeoplasmsMissionMolecularOncogenicPancreatic AdenocarcinomaPatientsPhosphorylationPre-Clinical ModelProcessRUNX1 geneReading FramesRegulationResearch ProposalsSamplingSignal TransductionSpecificitySpecimenSystemTP53 geneTestingTherapeuticTumor PromotersTumor SuppressionTumor Suppressor ProteinsWorkXenograft procedurebench to bedsidebonecell growthgenetic approachimprovedinsightloss of functionlung cancer cellmorphogensnew therapeutic targetnovelpancreatic differentiation 2 proteinpreventprogramsresponsesarcomasmall moleculetherapeutic targettranscription factortumortumorigenesisuncontrolled cell growthunpublished works
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 Our unpublished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.
项目概要
肿瘤抑制因子(TS)通过在多个水平发挥作用来调节细胞生长和死亡的平衡。放松管制
这些层次中的任何一个都可以促进肿瘤发生,影响癌症患者的生存和对当前疾病的反应
可用的治疗方法。因此,更好地理解这些过程并识别新颖的
TS 丢失的治疗目标是癌症生物学领域的一个优先事项。数十年的工作已经定义了如何
p14ARF(替代阅读框)TS 以 p53 依赖性方式发挥作用,以预防肿瘤发生。
然而,ARF 也以独立于 p53 的方式运行,以潜在地“备份 p53”,但其机制
仍然知之甚少。该领域重新流行了深入研究肿瘤抑制机制和
利用基础生物学来获得治疗机会。在此背景下,本研究计划的主要目标
的目的是定义 ARF(p53 丢失后重新激活)如何发挥作用来抑制肿瘤启动子程序。我们未发表的
研究已经明确了以前被忽视的 ARF 肿瘤抑制机制。首先,在 p53 丢失后,
重新激活的 ARF 选择性地靶向编码基因的聚合酶相关因子 1 复合物 (PAF1C)
促生长 GDF 和 BMP 配体可抑制异常细胞生长。其次,初级 p53-/- 中 ARF 的丢失
细胞去抑制 GDF/BMP 程序,导致 SMAD1/5 磷酸化和靶基因激活
(“致癌 GDF/SMAD 轴”),表明双 TS(p53 和 ARF)产生致癌脆弱性
损失成为替代治疗目标。然而,目前尚不清楚 ARF 如何在 ARF 中灭活 PAF1C。
基因特异性方式以及致癌 GDF/SMAD 轴是否具有任何诊断和治疗价值。
这项小额赠款提案旨在解决 ARF 如何以基因特异性方式灭活 PAF1C
抑制肿瘤促进程序并评估针对致癌基因的治疗价值
GDF/SMAD 计划。本提案中的工作以这些先前的发现和知识方面的关键差距为指导
检验 ARF 结合 Paf1 和基因特异性因子 RUNX1 以阻断 PAF1C 的中心假设
以基因特异性方式组装,从而抑制肿瘤启动子程序。测试底层
假设,我们将利用生化和遗传学方法以及临床和分子注释
临床前模型。具体来说,我们首先研究ARF如何结合Paf1和RUNX1来阻断PAF1C
以基因特异性方式组装(目标 1),然后探测肿瘤是否具有双 TS(p53 和 ARF)丢失
表现出致癌 GDF/SMAD 轴的重新激活并检查其治疗和诊断潜力(目标
2)。共同阐明 ARF 负向调节 PAF1C 依赖性肿瘤启动子的机制
转录程序将提高我们对重要生物过程的理解并提供替代方案
通过 ARF 和 p53 双重失活来靶向治疗 TS 丢失的机会(例如肉瘤、胰腺癌和
肺腺癌),这符合 NCI 的使命,即确定新的靶点以将这些发现从
到诊所的长凳。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ivan D'Orso其他文献
Ivan D'Orso的其他文献
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