Mip/LIN9 and Cell Proliferation

Mip/LIN9 和细胞增殖

• 批准号: 7905206
• 负责人: OSCAR R COLAMONICI
• 金额: $ 31.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905206
• 关键词: Address; Adult; Affect; Amino Acids; Animal Model; Animals; Antigens; B-Lymphocytes; Biological Process; Bypass; CDK2 gene; CDK4 gene; Caenorhabditis elegans; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Lineage; Cell Proliferation; Cell division; Cell physiology; Cells; Complex; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; DNA Repair; Defect; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Embryo; Embryonic Development; Eukaryota; Event; Family; Family member; G1 Arrest; G1 Phase; Genes; Genetic Transcription; Goals; Growth; Hand; Homologous Gene; Lead; Liver; Lobular Neoplasia; Malignant Neoplasms; Mammalian Cell; Mitosis; Modeling; Mus; Mutation; Oncogenes; Oncogenic; Organ; Pathway interactions; Phase; Phenotype; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Process; Proliferating; Protein Family; Proteins; RBL2 gene; RNA Interference; Regulation; Repression; Resistance; Retinoblastoma; Retinoblastoma Genes; Retinoblastoma Protein; Role; Series; Signal Transduction; Stimulus; T-Lymphocyte; TP53 gene; Testing; Testis; Tissues; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; base; cancer cell; cancer type; cell type; extracellular; gene function; in vivo; inhibitor/antagonist; knock-down; mature animal; member; mouse model; novel; overexpression; p107 protein; programs; protein function; public health relevance; research study; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The G1 phase of the cell cycle is the target of extracellular signals that regulate cell proliferation. Mitogenic stimuli are responsible for cell cycle progression via the orderly activation of cyclin-dependent kinases (CDKs) that inactivate members of the retinoblastoma or pocket protein family, pRB, p107 and p130. The understanding of the regulation of the G1 phase of the cell cycle is critical since alterations of its regulation could lead to unscheduled DNA synthesis and tumor formation. The pocket proteins form complexes with the E2F family members to regulate transcription of a specific set of genes, termed E2F-regulated genes, which are required for the passage into S-phase. CDK4,6 and CDK2 are responsible for the inactivation of the repressor activity that pRB/E2F1-3 and p107,p130/E2F4,5 exert on genes required for cell cycle progression. These repressor complexes contain other proteins that contribute to G0/G1 regulation. We recently demonstrated that a novel protein with homologs in all eukaryotes, Mip/LIN-9, participates in the regulation of cell cycle progression. In this application, we will test the hypothesis that Mip/LIN-9, like the pocket proteins, acts downstream of CDK4. We propose that the activity of this G1 kinase is responsible for the release of Mip/LIN-9 from the p107,p130/E2F4 repressor complex and that this step is critical for the association of Mip/LIN-9 with B-Myb is S-phase where both proteins function as transcriptional activators of the G2/M genes. We will also elucidate if Mip/LIN-9 is required for the activity of the repressor complex in G0. Finally, we will produce a new animal model with a complete deletion of the Mip/LIN-9 gene to determine its role in other cellular functions as well as in development. PUBLIC HEALTH RELEVANCE: The goal of this project is to characterize a protein termed Mip/LIN-9, which is responsible for the regulation of cell division and proliferation. This goal is relevant for the growth of all cell types but it is particularly relevant for cancer cells. The goals proposed in this project could produce importance advancement in understanding and treatment of different types of cancer.

描述（由申请人提供）：细胞周期的G1期是调节细胞增殖的细胞外信号的靶点。促有丝分裂刺激通过细胞周期蛋白依赖性激酶（CDK）的有序激活负责细胞周期进程，所述细胞周期蛋白依赖性激酶（CDK）激活视网膜母细胞瘤或口袋蛋白家族的成员pRB、p107和p130。对细胞周期G1期调控的理解至关重要，因为其调控的改变可能导致非程序性DNA合成和肿瘤形成。口袋蛋白与E2 F家族成员形成复合物，以调节一组特定基因（称为E2 F调节基因）的转录，这些基因是进入S期所需的。CDK 4，6和CDK 2负责pRB/E2 F1 -3和p107，p130/E2 F4，5对细胞周期进程所需基因施加的阻遏物活性的失活。这些阻遏物复合物含有其他有助于G 0/G1调节的蛋白质。我们最近证明，一种新的蛋白质与同源物在所有真核生物，Mip/LIN-9，参与细胞周期进程的调节。在本申请中，我们将检验Mip/LIN-9与口袋蛋白一样作用于CDK 4下游的假设。我们提出，该G1激酶的活性负责从p107、p130/E2 F4阻遏物复合物释放Mip/LIN-9，并且该步骤对于Mip/LIN-9与B-Myb在S期的关联是关键的，其中两种蛋白质都作为G2/M基因的转录激活因子发挥作用。我们还将阐明Mip/LIN-9是否是G 0期阻遏物复合物活性所必需的。最后，我们将产生一种新的动物模型，完全删除Mip/LIN-9基因，以确定其在其他细胞功能以及发育中的作用。 公共卫生相关性：该项目的目标是表征一种名为Mip/LIN-9的蛋白质，该蛋白质负责调节细胞分裂和增殖。这一目标与所有细胞类型的生长相关，但与癌细胞特别相关。该项目提出的目标可能会在理解和治疗不同类型的癌症方面产生重要的进步。