Fhit modulation of cell cycle progression and DNA damage response

Fhit 调节细胞周期进程和 DNA 损伤反应

• 批准号: 7413484
• 负责人: KAY HUEBNER
• 金额: $ 31.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413484
• 关键词: Allelic Imbalance; Apoptosis; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Proliferation; Cell physiology; Cells; Chromosome Fragile Sites; Condition; Cyclin D1; DNA Damage; DNA biosynthesis; DNA damage checkpoint; Data; Defect; Exposure to; FHIT gene; Genomic Instability; Goals; Growth; Hyperplasia; Induction of Apoptosis; Infection; Lesion; Malignant Neoplasms; Mus; Mutation; Nature; Oral; Oxidative Stress; PPP3CA gene; Pathway interactions; Process; Proteins; Research; Role; Stress; Upper digestive tract structure; Virus; base; cell transformation; gene therapy; mutant; prevent; response; survivin; tumor; tumor progression

Fhit modulation of cell cycle progression and DMA damage response It has recently been proposedthat in early preneoplastic lesions, DNA replication stress leads tc the DNA Damage Response (DDR), which elicits growth arrest and cell death. Thus, before occurrence o-' genomic instability and transformation, cells activate DNA damage response networks that delay or prevent cancer; mutations that compromise the checkpoints, such as defects in Atm or Atr pathway proteins, allcw escape from the checkpoint block, leading to tumor progression. Importantly, for the research proposed here, the early hyperplasias showed allelic imbalance at common fragile sites, particularly the FRA3B/FH1T locus. "Fragile site LOH was targeted during the period of maximal DDR and may be considered a "signature" of stalled replicationforks" (Gorgoulis et at, Nature 434:907-913, 2005). The researchproposed is based on the hypothesis that loss of the Fhit tumor suppressorvery early in the preneoplastic process, coincident with activation of the DNA damage response (DDR) checkpoint, effects critical cellular processes, cell proliferation, DNA damage response and apoptosis, that can tip the tBalance toward genome instability and tumor progression. The hypothesis is based on preliminary data demonstrating that Fhit-deficient cells show altered expression of cell,cycle, DNA damage response andapoptosis associated proteins and that Fhit over-expression modulates expression of Cyclin D1, Hus1, Chk1 jind Akt/mTor/Survivin. ¿; ¿ The goals of this project are to understand the mechanisms underlying Fhit modulation of these pathways by the following aims: 1) Examine the mechanism of Fhit down-modulation of Cyclin D1 level after infection of Fhit negsitive cells with AdenoFHIT and AdenoFHIT mutant viruses. ¿ 2) Determine the mechanisms through which Fhit modulates" the level of Hus1, pChkl and the CNA damage response pathway by manipulation of Fhit .expression in Fhit-deficient cells. 3) Examine the role of Fhit in induction of apoptosis after AdenoFHIT and AdenoFHIT mutant viius infection of Fhit-deficient cells and exposure to oxidative stress conditions. 4) Define the sequenceof modulation of expression of cell.cycle, DDR and apoptosis associated proteins in early oral and upper gastrointestinal tract lesions of Fhit-deficient mice before and after FHIT replacement by AdenoFHIT oral gene therapy. ,

Fhit调控细胞周期进程和DMA损伤反应 最近有人提出，在早期癌前病变中，DNA复制应激导致DNA损伤。 损伤反应（DDR），其引起生长停滞和细胞死亡。因此，在发生O-“基因组”之前， 不稳定性和转化，细胞激活DNA损伤反应网络，延迟或预防癌症; 危及检查点的突变，如Atm或Atr通路蛋白的缺陷， 导致肿瘤进展。重要的是，对于这里提出的研究， 早期增生在常见脆性位点，特别是FRA 3B/FH 1 T位点表现出等位基因不平衡。 脆性位点洛是在最大DDR期间发生的，可被认为是 停滞的复制叉”（Gorgoulis等人，Nature 434：907-913，2005）。 这项研究是基于这样一个假设，即Fhit肿瘤抑制因子的缺失在肿瘤发生的早期就已经存在。 肿瘤前过程，与DNA损伤反应（DDR）检查点的激活一致， 关键的细胞过程，细胞增殖，DNA损伤反应和细胞凋亡，这可能会改变tBalance 基因组不稳定性和肿瘤进展。该假设基于初步数据， Fhit缺陷细胞表现出细胞表达、细胞周期、DNA损伤反应和凋亡的改变， Fhit过表达调节细胞周期蛋白D1、Hus 1、Chk 1金德和其他相关蛋白的表达 Akt/mTor/Survivin。？;？ 本项目的目标是了解Fhit调节这些通路的机制 其目的如下： 1)探讨Fhit下调Fhit阳性细胞Cyclin D1表达的机制 AdenoFHIT和AdenoFHIT突变体病毒。¿ 2)确定Fhit调节”Hus 1、pChk 1和CNA水平“的机制 通过操纵Fhit缺陷细胞中的Fhit表达来破坏应答途径。 3)检测Fhit在AdenoFHIT和AdenoFHIT突变体病毒感染后诱导细胞凋亡中的作用 Fhit缺陷细胞的感染和暴露于氧化应激条件。 4)明确细胞周期、DDR和凋亡相关蛋白表达的调控顺序 在FHIT前后FHIT缺陷小鼠早期口腔和上消化道病变中 AdenoFHIT口服基因治疗替代。,