Role of Alternative Mxi1 Isoforms in the Myc Network

描述：（由申请人提供）MYC原癌基因家族起着重要作用。 在对促有丝分裂刺激的反应和对 在正常和恶性细胞中增殖。c-Myc蛋白过度表达是一种 伯基特淋巴瘤的标志，N-MYC扩增是一个关键的 神经母细胞瘤的预后因素MYC基因的表达也被解除调节， 许多其他癌症，但调节Myc活性的分子机制是 只是部分阐明。本提案将具体探讨以下方面的作用： Mxii和MxiO，两个Myc家族成员，在调节两个c- 和N-Myc。Myc作为一种转录因子，调控着多种相关基因的表达， 对细胞生长、分裂和凋亡的影响。与Myc相反，Mxii抑制 一些Myc调控基因的转录，抵消Myc的作用。 因此，Mxii是Myc拮抗剂。我们已经表明，Mxii表达导致 生长停滞，抑制体外细胞增殖。所以我们 假设Mxii活性降低可能增强Myc依赖性 增殖我们最近发现了MxiO，一种新的， 缺乏Mxii的生长抑制活性的Mxii同种型。而MxiO和 Mxii在许多细胞系和组织中伴随表达，相对的 肿瘤和肿瘤细胞系中的MxiO水平高于正常细胞。 MxiO和Mxii水平的这种变化表明，Myc抑制剂 Mxii的活性可由MxiO调节。我们假设MxiO是Mxii 拮抗剂这种单一基因产生蛋白质产物的概念， 在Bcl-x的情况下， （Bcl-xL对比Bcl-xS）和Ink 4a（p16对比p14）。在这份提案中，我们将探讨 MxiO和Mxil彼此之间以及与Myc之间的相互作用， 细胞增殖和瘤形成，通过设置以下具体 目的：（1）表征MxiO的生物活性;（2）确定MxiO如何 根据我们的经验，MxiO和Mxii的表达是协调调节的。 用Mxii启动子来确定调节表达的因子 通过MxiO启动子;（3）确定生长调节机制， 在Myc的背景下，我们将使用c-Myc诱导的MxiO和Mxii的模型。 转化，以及N-Myc依赖性神经母细胞瘤增殖， 探索这些相互作用，并研究基因表达模式;（4） 评价特异性失活mxii或mxiO在小鼠中的体内作用。 转基因小鼠通过这些研究，我们将更好地了解 这些Mxii亚型在涉及的复杂Myc信号通路中的作用 在细胞生长调节和肿瘤形成方面。

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.