PAF-Remodeled DREAM Complex in Cancer and Regeneration

项目总结/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 伴侣、RB样、E2 F和多外阴B类（DREAM）复合物，在生殖系统中也称为DRM复合物。 秀丽隐杆线虫与dREAM复合体在果蝇中是一种进化上保守的细胞 周期调节多蛋白复合物。与辅激活子和辅抑制子相关， 复合物直接调节与细胞周期和细胞静止直接相关的各种基因的表达。 然而，目前还不清楚DREAM复合物在生理和病理条件下如何调节。 增殖细胞核抗原（PCNA）相关因子（PAF;也称为PCLAF/KIAA 0101）是一种高度表达的细胞因子。 在许多癌症中上调，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 可能通过重塑DREAM复合物，对细胞的静止退出和细胞增殖是必不可少的。 基于我们以前的研究和初步结果，我们假设PAF重塑了抑制性的 DREAM用于细胞静止退出和增殖以维持和激活肺中的细胞干细胞 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： 1)解读PAF-改造DREAM复合物的分子机制;目的2）确定 PAF和PAF表达细胞在肺癌和组织再生中的病理和生理作用。 这项研究将探讨PAF如何通过重塑DREAM复合体来绕过细胞静止期 并加速细胞增殖。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后重新进入细胞周期。这项研究将建立一个 通过揭示梦的重塑如何在肺癌的启动和再生的新范式 复合物有助于病理（癌症）和生理（再生）过程。而且 本研究的完成可能提出PAF-DREAM轴作为肺癌的靶向易感性。

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.