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Nuclear Accumulation of D-type Cyclins and Oncogenesis

D 型细胞周期蛋白的核积累和肿瘤发生

基本信息

批准号：
10013443
负责人：
John Alan Diehl
金额：
$ 29.12万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013443
关键词：
Acute Address Alanine Alleles Biochemical Biological Burkitt Lymphoma C-terminal CCND1 gene CCND2 gene CDK4 gene Cancer Model Cell Nucleus Cells Codon Nucleotides Coupled Cyclin A Cyclin D1 Cyclins Cytoplasm DNA Data Detection Development Engineering Esophageal Exhibits Exons Frequencies G1 Phase Generations Genomic Instability Grant Hematopoietic Homeostasis Human Impairment Knock-in Mouse Knowledge Lymphoma Malignant Neoplasms Modeling Molecular Multiple Myeloma Mus Mutate Mutation Neoplasms Non-Hodgkin&apos s Lymphoma Nuclear Nuclear Export Oncogenes Oncogenic PTEN gene Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Polyubiquitination Property Proteomics Refractory Regulation Resolution Role S phase Somatic Mutation Specificity TP53 gene Therapeutic Threonine Tissues Ubiquitin Ubiquitin-mediated Proteolysis Pathway Uterine Cancer Work arginine methyltransferase cancer genomics cohesion cyclin D3 experimental study human cancer mouse model human model inducible gene expression melanoma mouse model mutant neoplastic novel overexpression prevent promoter tumor tumor initiation tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

While cyclin D1 is overexpressed in cancer, wild type cyclin D1 is poorly oncogenic. Through work supported by this grant, we have pioneered the resolution to this paradox. Importantly, our work has revealed a paradigm wherein cyclin D1 accumulates in the nucleus during G1 phase; however, at the G1/S boundary, phosphorylation of a single threonyl residue, Thr-286, by GSK-3b triggers cyclin D1 nuclear export and its cytoplasmic ubiquitin-mediated proteolysis. A non-phosphorylatable mutant, D1T286A, is constitutively nuclear, refractory to poly- ubiquitination and has potent oncogenic properties. An instrumental finding during the previous four years was the demonstration that accumulation of active nuclear cyclin D1/CDK4 kinase during S-phase triggers DNA re-replication, induces genomic instability and inactivation of p53; all a consequence of its capacity to activate the arginine methyltransferase PRMT5. It is now evident that cyclin D1 is subject to frequent mutations that directly inhibit Thr-286 phosphorylation, thereby demonstrating that cyclin D1 as a driver oncogene. Examples include uterine cancer, esophageal, melanoma and multiple myeloma. Since current models depend on overexpression of mutant alleles from ectopic promoters, we have generated a new model that allows inducible expression of the mutant D1T286A from its endogenous promoter. We hypothesize that expression of cyclin D1T286A from its endogenous promoter will drive neoplastic growth and will permit the generation of mouse models of human cancer that mimic somatic mutation of cyclin D1. In addition, while much effort has been focused on cyclin D1 due to its frequent dysregulation in cancer, it is now evident that cyclin D3 is subject to an analogous mutation in Burkitt’s lymphoma where the conserved c-terminal phosphorylation site, Thr-283 in D3, is mutated to a non-phosphorylatable residue. Such mutations co-occur with myc- translocations at a frequency approaching 50%. This revelation highlights a gap in knowledge regarding how phosphorylation of D3 contributes to its regulation and cell homeostasis. We therefore hypothesize that Thr-283 phosphorylation directs cyclin D3 for export to the cytoplasm where it is ubiquitylated and degraded. These gaps in knowledge will be directly addressed through three cohesive aims: Aim 1 will determine the neoplastic activity of cyclin D1T286A using an inducible knockin mouse model that permits expression from its endogenous promoter; Aim 2 will determine the role of Fbxl8 in ubiquitylation of Thr-283 phosphorylated cyclin D3; Aim 3 will determine the tumor suppressive function of Fbxl8 and whether non-phosphorylatable cyclin D3T283A exhibits enhanced ability to drive lymphoma.

细胞周期蛋白D1在癌症中过度表达，而野生型细胞周期蛋白D1的致癌性较差。通过