Role of Alternative Mxi1 Isoforms in the Myc Network

替代 Mxi1 同工型在 Myc 网络中的作用

基本信息

批准号：
6771668
负责人：
DANIEL STEVEN WECHSLER
金额：
$ 28.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6771668
关键词：
RNA splicing gene targeting genetic promoter element genetically modified animals laboratory mouse neoplastic growth neuroblastoma oncoproteins protein isoforms protein protein interaction transcription factor

项目摘要

DESCRIPTION: (provided by applicant) The MYC proto-oncogene family plays a central role in the response to mitogenic stimuli and the control of proliferation in normal and malignant cells. c-Myc protein overexpression is a hallmark of Burkitt's lymphoma, and N-MYC amplification is a critical prognostic factor in neuroblastoma. MYC gene expression is also deregulated in many other cancers, but the molecular mechanisms that regulate Myc activity are only partly elucidated. This proposal will specifically investigate the role of Mxii and MxiO, two Myc family members, in modulating the activity of both c- and N-Myc. As a transcription factor, Myc regulates expression of genes related to cell growth, division and apoptosis. In contrast to Myc, Mxii represses transcription of some Myc-regulated genes, counteracting the effects of Myc. Thus, Mxii is a Myc antagonist. We have shown that Mxii expression results in growth arrest, suppressing cell proliferation in vitro. Therefore, we hypothesize that reduced Mxii activity is likely to potentiate Myc-dependent proliferation. We recently identified MxiO, a novel, alternatively transcribed Mxii isoform that lacks the growth suppressive activity of Mxii. While MxiO and Mxii are concomitantly expressed in many cell lines and tissues, the relative levels of MxiO are higher in tumors and tumor cell lines than in normal cells. This variation in levels of MxiO and Mxii suggests that the Myc-inhibitory activity of Mxii may be modulated by MxiO. We postulate that MxiO is an Mxii antagonist. This notion of a single gene giving rise to protein products with alternative biological activities is well established in the case of Bcl-x (Bcl-xL vs. Bcl-xS) and Ink4a (p16 vs. p14). In this proposal, we will explore the interactions of MxiO and Mxil with each other and with Myc, in the context of both cell proliferation and neoplasia, by setting the following Specific Aims: (1) Characterize the biological activity of MxiO; (2) Determine how expression of MxiO and Mxii are coordinately regulated, using our experience with the Mxii promoter to determine the factors that regulate expression through the MxiO promoter; (3) Determine mechanisms of growth regulation by MxiO and Mxii in the context of Myc-we will use models of c-Myc-induced transformation, as well as N-Myc-dependent neuroblastoma proliferation to explore these interactions, and also study patterns of gene expression; and (4) Evaluate the in vivo effects of specifically inactivating mxii or mxiO in transgenic mice. Through these studies, we will gain a better understanding of the role of these Mxii isoforms in the complex Myc signaling pathways involved in cell growth regulation and neoplasia.

描述：（由申请人提供）MYC原始癌基因家族扮演中心作用在对有丝分裂刺激的反应中正常和恶性细胞中的增殖。 C-myc蛋白过表达是伯基特淋巴瘤和N-MYC扩增的标志是关键神经母细胞瘤的预后因素。 MYC基因表达也在许多其他癌症，但是调节MYC活性的分子机制是仅部分阐明。该建议将专门研究 MXII和MXIO，两个MYC家庭成员，调节两个C-的活性和n-myc。作为转录因子，MYC调节基因相关的表达细胞生长，分裂和凋亡。与MYC相反，MXII压抑某些MYC调节基因的转录，抵消了MYC的作用。因此，MXII是MYC的拮抗剂。我们已经表明MXII表达导致生长停滞，体外抑制细胞增殖。因此，我们假设减少的MXII活性可能会增强MYC依赖性增殖。我们最近确定了MXIO，这是一部小说，替代转录缺乏MXII的生长活性的MXII同工型。而mxio和 MXII同时在许多细胞系和组织中表达在肿瘤和肿瘤细胞系中MXIO的水平高于正常细胞。 MXIO和MXII水平的这种变化表明MYC抑制性 MXII的活性可能由MXIO调节。我们假设MXIO是MXII 对手。单个基因的这种概念与在BCL-X的情况下，替代生物学活动已建立（BCL-XL与BCL-XS）和Ink4a（p16 vs. p14）。在此提案中，我们将探索 MXIO和MXIL彼此之间以及MYC的相互作用通过设置以下特定的细胞增殖和肿瘤目的：（1）表征MXIO的生物学活性；（2）确定如何使用我们的经验，MXIO和MXII的表达进行了协调调节使用MXII启动子来确定调节表达的因素通过MXIO启动子；（3）确定通过 MXIO和MXII在MYC-WE的背景下将使用C-MYC诱导的模型转化以及N-MYC依赖性神经母细胞瘤增殖到探索这些相互作用，还研究基因表达的模式；（4）评估特异性失活的MXII或MXIO的体内效应转基因小鼠。通过这些研究，我们将更好地理解这些MXII同工型在涉及的复杂MYC信号通路中的作用在细胞生长调节和肿瘤中。