A NOVEL MECHANISM OF TCL1 TUMORIGENESIS

TCL1肿瘤发生的新机制

基本信息

批准号：
7367797
负责人：
MICHAEL A TEITELL
金额：
$ 27.03万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367797
关键词：
Accounting Acquired Immunodeficiency Syndrome Address Antibodies Antibody Specificity B lymphoid malignancy B-Cell Lymphomas B-Lymphocytes Binding Cancer Etiology Cell membrane Chromosomal Rearrangement Complex Cytidine Deaminase Dendritic Cells Development Enzymes Family member Gene Expression Gene Family Grouping Healthcare Hematologic Neoplasms Hematopoietic Neoplasms Histocompatibility Testing Immune Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation In Vitro Investigation Knockout Mice Lead Ligands Link Lymphoid Lymphoid Cell Lymphomagenesis Malignant Neoplasms Mature B-Lymphocyte Mediating Messenger RNA Minor Myelogenous Oncogenic PTEN gene Pathway interactions Patients Phosphotransferases Polyribonucleotide Nucleotidyltransferase Positioning Attribute Process Proto-Oncogene Proteins c-akt Proto-Oncogenes RNA Reaction Reagent Sampling Specificity Structure of germinal center of lymph node System T-Cell Leukemia T-Cell Lymphoma T-Cell Prolymphocytic Leukemia T-Lymphocyte TCL1B gene Testing Time Tissues Transgenic Mice Transgenic Model Transgenic Organisms Tumor Suppressor Proteins Work World Health Organization base carcinogenesis cell growth cell transformation chronic T-cell leukemia cohort in vivo lymphoid neoplasm mouse model novel tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): We propose a new mechanism for TCL1 (T cell leukemia-1) induction of lymphoid cancers. The assumption has been that aberrant TCL1 expression promotes inappropriate AKT (protein kinase-B) activation to cause transformation. However, the extent of TCL1-augmented AKT activation is comparable to the degree of enhanced AKT activation induced by targeted deletion of the PTEN tumor suppressor in B cells. Most notably, our TCL1 transgenic mice rapidly develop mature B cell malignancies while conditional PTEN-null mice never form B cell cancers. These observations lead us to hypothesize that TCL1-mediated AKT augmentation has, at most, a minor tumorigenic effect. We cannot, however, exclude the possibility that TCL1 alters the target specificity of AKT and we address this issue briefly in this proposal. Previously, we showed that a cytoplasmic membrane factor augmented TCL1/AKT interactions. We subsequently searched for new TCL1-interacting partners in flag-tagged TCL1 co-IP reactions. Surprisingly, we identified the RNA degrading enzyme polynucleotide phosphorylase (PNPase) as the sole TCL1 binding partner in lymphoid cells. We will determine whether or not PNPase is the TCL1/AKT interaction-augmenting factor. We favor the idea that PNPase/TCL1 interactions mediate TCL1-induced tumorigenesis through TCL1 stabilization of PNPase target mRNAs rather than by effecting AKT/TCL1 interactions. Testing this hypothesis is the main aim of this proposal. We provide preliminary evidence that TCL1/PNPase interactions block the processing of specific mRNAs. As such, TCL1 may be a natural PNPase ligand that regulates developmental gene expression by altering mRNA turnover by PNPase. When dysregulated, we predict TCL1 inappropriately stabilizes specific mRNAs destined for degradation, providing a novel mechanism of aberrant gene expression resulting in transformation. The most compelling candidate target mRNA is AID, since persistent AID hypermutation could account for the broad spectrum of germinal center-derived B cell cancers in our TCL1 transgenic mouse model. The specific aims in this proposal form an investigation of the mechanism of TCL1-mediated transformation, focusing on functional consequences of interactions between TCL1, PNPase and to a lesser extent AKT in vitro and in vivo.

描述（由申请人提供）：我们提出了一种TCL1（T细胞白血病1）诱导淋巴癌的新机制。该假设是异常TCL1表达促进不适当的Akt（蛋白激酶-B）激活引起转化。然而，TCL1增强的Akt激活的程度与B细胞中PTEN肿瘤抑制器的靶向缺失引起的增强Akt激活的程度相当。最值得注意的是，我们的TCL1转基因小鼠迅速发展成熟的B细胞恶性肿瘤，而条件PTEN-NULL小鼠永远不会形成B细胞癌。这些观察结果使我们假设TCL1介导的Akt增强最多具有较小的肿瘤效应。但是，我们不能排除TCL1改变AKT的目标特异性的可能性，我们在此提案中简要介绍了此问题。以前，我们表明细胞质膜因子增强了TCL1/AKT相互作用。随后，我们在标记为标记的TCL1 Co-IP反应中搜索了新的TCL1相互作用伙伴。令人惊讶的是，我们确定RNA降解酶多核苷酸磷酸化酶（PNPase）是淋巴样细胞中唯一的TCL1结合伴侣。我们将确定PNPase是否是TCL1/AKT相互作用因子。我们赞成这样一种观念，即PNPase/TCL1相互作用通过PNPase靶标mRNA而不是通过影响AKT/TCL1相互作用来介导TCL1诱导的肿瘤发生。检验该假设是该提议的主要目的。我们提供了TCL1/PNPase相互作用阻止特定mRNA的处理的初步证据。因此，TCL1可以是天然PNPase配体，通过改变PNPase的mRNA转换来调节发育基因表达。当失调时，我们预测TCL1不适当地稳定了原定降解的特定mRNA，从而提供了一种新颖的基因表达的机制，导致转化。最引人注目的候选目标mRNA是AID，因为持续的辅助超名可以解释我们的TCL1转基因小鼠模型中生发中心衍生的B细胞癌的广泛谱。该提案中的具体目的构成了对TCL1介导的转化机理的研究，重点是TCL1，PNPase之间的相互作用以及在体外和体内较小程度的AKT。