PAF-Remodeled DREAM Complex in Cancer and Regeneration

PAF 重塑的 DREAM 复合物在癌症和再生中的作用

• 批准号: 10400151
• 负责人: Jae-Il Park
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-09 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400151
• 关键词: Address; Attention; Biology; Bypass; Caenorhabditis elegans; Cancer Biology; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Complex; DNA Repair; DNA biosynthesis; Diagnosis; Dimerization; Dreams; Drosophila melanogaster; Engineering; Epigenetic Process; Fostering; Gene Expression; Genes; Genetic Transcription; Genetically Engineered Mouse; Health; Human; Lead; Lung; Lung diseases; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mission; Mitotic; Modeling; Molecular; Molecular Biology; Molecular and Cellular Biology; Multiprotein Complexes; Natural regeneration; Normal Cell; Pathologic; Physiological; Process; Proliferating Cell Nuclear Antigen; Proteins; Proteomics; Public Health; Research; Research Personnel; Resources; Role; Somatic Cell; Testing; Transactivation; United States National Institutes of Health; base; cancer cell; cancer initiation; genetic corepressor; in vivo; innovation; lung cancer prevention; lung regeneration; mouse genetics; stem; stem cell biology; stem cells; stemness; tissue injury; tissue regeneration; transcriptomics; tumorigenesis

PROJECT SUMMARY/ABSTRACT The somatic cells remain quiescent upon terminal differentiation. Perturbation of this process can lead to cell quiescence exit and proliferation, which is implicated in cancer and tissue regeneration. The dimerization partner, RB-like, E2F, and multi-vulval class B (DREAM) complex, also called the DRM complex in Caenorhabditis elegans and dREAM complex in Drosophila melanogaster, is an evolutionarily conserved cell cycle-regulatory multiprotein complex. In association with co-activators and co-repressors, the DREAM complex directly modulates the expression of various genes directly related to cell cycle and cell quiescence. However, it is unknown how the DREAM complex is regulated in the physiological and pathological conditions. Proliferating cell nuclear antigen (PCNA)-associated factor (PAF; also known as PCLAF/KIAA0101) is highly upregulated in many cancers but barely expressed in normal cells. Our comprehensive approaches, including molecular and cellular biology, mouse genetics, proteomics, and transcriptomics, found that PAF is indispensable for cell quiescence exit and cell proliferation possibly by remodeling the DREAM complex. Based on our previous studies and preliminary results, we hypothesize that PAF remodels the repressive DREAM for cell quiescence exit and proliferation for the maintenance and activation of cell stemness in lung cancer and lung tissue regeneration. This central hypothesis will be tested by pursuing two specific aims: Aim 1) Decipher the molecular mechanism of the PAF-remodeled DREAM complex; Aim 2) Determine the pathological and physiological roles of PAF and PAF-expressing cells in lung cancer and tissue regeneration. The proposed study will address how PAF remodels the DREAM complex for bypassing the cell quiescence and accelerating cell proliferation. Similarly, how stem and facultative progenitor cells become active/mitotic for tissue regenerating will be addressed by testing the working model - ‘PAF-remodeled DRAEM complex induces the cell cycle re-entry of the stem and progenitor cells upon tissue injury’. This study will establish a new paradigm in lung cancer initiation and regeneration by revealing how the remodeling of the DREAM complex contributes to pathological (cancer) and physiological (regeneration) processes. Moreover, the completion of this study may propose the PAF-DREAM axis as a targetable vulnerability of lung cancer.

项目摘要/摘要 体细胞在终末分化时保持静止。这一过程的扰动可能导致细胞 静止退出和增殖，这与癌症和组织再生有关。二聚化 合作伙伴、类RB、E2F和多外阴B类(梦想)复合体，也称为DRM复合体 黑腹果蝇秀丽线虫与梦境复合体是一种进化保守的细胞 周期调节多蛋白复合体。在共同激活者和共同抑制者的共同作用下，梦想 复合体直接调控与细胞周期和细胞静止直接相关的各种基因的表达。 然而，目前尚不清楚梦复合体在生理和病理条件下是如何调节的。 增殖细胞核抗原相关因子(PAF；也称为PCLAF/KIAA0101)高度依赖于 在许多癌症中表达上调，但在正常细胞中几乎不表达。我们的综合方法，包括 分子和细胞生物学，小鼠遗传学，蛋白质组学和转录组学，发现PAF是 对于细胞静止退出和细胞增殖来说是必不可少的，可能是通过重塑梦境复合体。 根据我们以前的研究和初步结果，我们假设PAF重塑了抑制 梦想细胞静止退出和增殖，以维持和激活肺细胞干细胞 癌症和肺组织再生。这一中心假设将通过追求两个具体目标来检验：目标 1)破译PAF重塑的DREAM复合体的分子机制；目的2)确定 PAF及其表达细胞在肺癌和组织再生中的病理生理作用 这项拟议的研究将解决PAF如何重塑梦境复合体以绕过细胞静止 加速细胞增殖。同样，干细胞和兼性祖细胞如何变得活跃/有丝分裂 组织再生将通过测试工作模型--PAF重塑的DRAEM复合体来解决 诱导干细胞和祖细胞在组织损伤时重新进入细胞周期。这项研究将建立一个 通过揭示梦想的重塑，肺癌启动和再生的新范式 复合体有助于病理(癌症)和生理(再生)过程。此外， 这项研究的完成可能会提出PAF-DREAM轴是肺癌的靶向易损性。