Nuclear Accumulation of Cyclin D1 and Oncogenesis

细胞周期蛋白 D1 的核积累和肿瘤发生

基本信息

批准号：
7760068
负责人：
John Alan Diehl
金额：
$ 29.11万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760068
关键词：
Alleles Apoptosis B-Cell Lymphomas B-Lymphocytes Binding Bone Marrow Involvement Cancerous Categories Cell Cycle Cell Cycle Progression Cell Nucleus Cell Proliferation Cells Chromosomal translocation Cyclin D1 Cyclins Cytoplasm DNA damage checkpoint Data Development Diagnosis Disease Double Strand Break Repair Engineering F Box Domain F-Box Proteins Frequencies Gastrointestinal tract structure Genomic Instability Grant Growth Homeostasis Human In Vitro Laboratories Lymphoid Lymphoma Lymphomagenesis Maintenance Malignant Neoplasms Mantle Cell Lymphoma Mus Mutation Neoplasms Neoplastic Cell Transformation Normal Cell Nuclear Nuclear Export Oncogenic Pathway interactions Phase Phenotype Phosphorylation Phosphotransferases Pre-Replication Complex Property Protein Isoforms Proteolysis RNA Splicing Refractory Regulatory Pathway Research Research Personnel Resolution Role Signal Pathway Signal Transduction Specificity Spleen TP53 gene Testing Transgenic Mice Tumor Suppression Tumor-Derived Ubiquitin Ubiquitin-mediated Proteolysis Pathway Ubiquitination Work cell growth cell transformation effective therapy mouse model multicatalytic endopeptidase complex mutant neoplastic cell novel outcome forecast overexpression programs research study stem tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of my research centers on elucidation of the mechanisms whereby extra-cellular signals are sensed by the cell cycle machinery and regulate cell cycle progression in normal versus tumor cells. This information will provide the framework necessary to elucidate how growth regulatory pathways are subverted in neoplasia. Our current studies focus on how growth-signaling pathways regulate the mitogenically responsive D-type cyclins and more specifically how these pathways regulate accumulation of an active, nuclear cyclin D1-dependent kinase in normal versus cancerous cells. The noted overexpression of cyclin D1 in multiple human cancers highlights the importance of elucidating the mechanisms that regulate cyclin D1 activity. Of the various cancers in which deregulated cyclin D1 activity is implicated, mantle cell lymphoma (MCL) is one of the most devastating. Cyclin D1 is aberrantly expressed in MCL due to the 11:14 chromosomal translocation. MCL represents a distinct category of B-cell lymphoma that presents as a disseminated disease with involvement of bone marrow, spleen, and, sometimes, gastrointestinal tract. Because there is no effective treatment, MCL has a poor prognosis with an average survival of 3.5 years post-diagnosis. Although cyclin D1 is overexpressed in MCL, have yet to establish any mouse models that recapitulate cyclin D1-dependent lymphomagenesis. We propose this reflects inadequate understanding of how cyclin D1 is regulated post-translationally in normal versus tumor cells. Indeed we have previously demonstrated that cyclin D1-dependent cell transformation in vitro depends upon its nuclear retention during S-phase. We therefore generated transgenic mice wherein a nuclear export defective, and thus constitutively nuclear, cyclin D1 allele is targeted to lymphoid compartments. Expression of this cyclin D1 allele specifically promotes B-cell lymphoma. Lymphoma development correlates with p53 loss. We hypothesize that lymphomagenesis triggered by constitutively nuclear cyclin D1 mutants is restricted by p53- dependent apoptosis and therefore dependent upon inactivation of p53. The experiments described in this proposal will determine the mechanisms whereby D1-T286A expression triggers p53 activation, establish the role of p53 in tumor suppression, and evaluate the contribution of nuclear cyclin D1 isoforms to growth and proliferation of mantle cell lymphoma-derived cells.

描述（由申请人提供）：我的研究中心关于阐明机制的长期目标，从而通过细胞周期机制感知细胞外信号并调节正常细胞与肿瘤细胞的细胞周期进程。该信息将提供必要的框架，以阐明在肿瘤中如何颠覆生长调节途径。我们目前的研究集中于生长信号途径如何调节有丝分裂响应的D型细胞周期蛋白，更具体地说是这些途径如何调节正常细胞中活性的，核细胞周期蛋白D1依赖性激酶的积累。多种人类癌症中细胞周期蛋白D1的过表达强调了阐明调节细胞周期蛋白D1活性的机制的重要性。在涉及失调的细胞周期蛋白D1活性的各种癌症中，地幔细胞淋巴瘤（MCL）是最毁灭性的。由于11:14染色体易位，Cyclin D1在MCL中异常表达。 MCL代表了B细胞淋巴瘤的一种不同类别，该类别呈现为一种传播疾病，伴有骨髓，脾和有时是胃肠道。由于没有有效的治疗方法，MCL的预后较差，诊断后平均存活率为3.5年。尽管Cyclin D1在MCL中过表达，但尚未建立任何概括Cyclin d1依赖性淋巴细胞化的小鼠模型。我们提出，这反映出对cyclin D1在正常细胞和肿瘤细胞中如何在后翻译中如何调节的理解不足。实际上，我们先前已经证明了细胞周期蛋白D1依赖性细胞在体外取决于其在S期间的核保留率。因此，我们产生了转基因小鼠，其中核输出缺陷并因此具有组成型核细胞周期蛋白D1等位基因针对淋巴室。该细胞周期蛋白D1等位基因的表达特异性促进了B细胞淋巴瘤。淋巴瘤发育与p53损失相关。我们假设由组成型核细胞周期蛋白D1突变体触发的淋巴作用受到p53依赖性细胞凋亡的限制，因此取决于p53的失活。该提案中描述的实验将确定D1-T286A表达触发p53激活，确定p53在肿瘤抑制中的作用的机制，并评估核细胞周期蛋白D1同型对地幔细胞淋巴瘤衍生细胞的生长和增殖的贡献。