Characterization of Pathways Controlling Cancer at the Level of Gene Regulation

描述(由申请人提供)：该计划的一个主要优势是将基因调控的变化与小鼠癌症模型相结合，并将这些结果与人类癌症联系起来。本计划的总体目标是研究短和长非编码RNA在癌症发生发展中的作用，以及Rb-E2F途径在细胞死亡和恶性肿瘤中的重要性。MiRNAs可能与一半的mRNAs相互作用，将其中大多数mRNAs的表达水平抑制不到两倍，但在小鼠模型中仍明显调节癌症的发展。这些小RNA调节生长和细胞死亡基因，这两个基因都是肿瘤生长的调节器，它们还塑造发育过渡。该计划的第一个总体目标是调查miRNA功能丧失对细胞存活、发育过程和恶性肿瘤发展的影响。这三个项目正在研究miRNAs在基因调控中的一般作用，包括它们的作用机制，所有miRNAs缺失的后果，以及miRNAs与间叶性肿瘤和干细胞分化的关系。靶向小鼠遗传学将被用来研究miRI43-145簇在发育和肿瘤抑制中的作用。这将涉及探索激活这一家族的miRNAs在 体内的肿瘤。第二个总体目标是探索其他类型的非编码RNA在正常和恶性细胞中的作用。在寻找RNAi相关转录调控的过程中，非编码RNA的群体将被描述为DICER缺失和肿瘤细胞。这包括进一步研究核中可能的ArgAerte功能，以及由大多数启动子通过发散转录产生的非编码RNA的作用。由p53调控的大的介入性非编码RNA(LincRNAs)。它们在肿瘤生物学中的作用将使用靶向小鼠遗传学进行研究。第三个总体目标是研究肿瘤抑制基因Rb和P53与非编码RNA在控制癌症中的相互作用以及细胞分化状态的可塑性。Rb和miRNAs在发育转变和维持细胞状态中的关系将被研究。Rb和miRNAs在DNA损伤后诱导细胞死亡的相互作用和参与也将被研究。

DESCRIPTION (provided by applicant): A major strength of the Program is the integration of changes in gene regulation with mouse models of cancer and relating these results to human cancer. The overall goals of the current Program is to investigate the roles of both short and long non-coding RNAs in the development of cancer and the importance of the Rb-E2F pathway in cell death and malignancy. miRNAs probably interact with half of all mRNAs, suppress the level of expression of most of these mRNAs by less than two fold, and yet clearly modulate the development of cancer in mouse models. These small RNAs regulate growth and cell death genes, both modulators of tumor growth, and they also shape developmental transitions. The first Overall Aim of the Program is to Investigate the effects of loss of miRNA functions on cell viability, developmental processes and the development of malignancies. The three projects are investigating the general roles of miRNAs in gene regulation including their mechanisms of action, the consequence of loss of all miRNAs in Dicer null cell lines, and the relationship between miRNAs and differentiation of mesenchymal tumors and stem cells. Targeted mouse genetics will be used to investigate the roles of miRI43-145 cluster in development and tumor suppression. This will involve exploration of the effects of activation of this family of miRNAs in tumors in vivo. The second Overall Aim is to Explore the roles of other types of non-coding RNAs in normal and malignant cells. The population of non-coding RNAs will be characterized in Dicer null and tumor cells in search of RNAi-related transcriptional regulation. This includes further investigation of possible Argonaute functions in the nucleus and the roles of non-coding RNAs generated from most promoters by divergent transcription. The large intervening non-coding RNAs (lincRNAs) regulated by p53. and their roles in tumor biology will be investigated using targeted mouse genetics. The third Overall Aim is to investigate the interactions of tumor suppressor genes Rb and p53 and non-coding RNAs in control of cancer and the plasticity of the differentiation state of cells. The relationship of line RNAs and p53 and of Rb and miRNAs in developmental transition and in maintaining cell state will be investigated. The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied.