MOLECULAR MECHANISMS OF TRANSFORMATION BY AP 1 PROTEINS

Fos和Jun基因家族编码一系列蛋白质， 转录因子AP-1。的致癌潜能 这种转录因子的例子是， 家族最初是通过它们在基因组中的存在来确定的， 致瘤逆转录病毒。Fos-Jun复合体是 包括致癌酪氨酸激酶的信号转导途径 和ras癌基因，AP-1活性是由激活 酪氨酸激酶或ras活性。因此，似乎有可能， 了解肿瘤发生的分子机制， AP-1蛋白的转化也将有助于阐明 是这些癌蛋白引起恶性转化的基础。虽然 肿瘤分子机制的研究进展 Fos和Jun蛋白的形成已经实现，几个关键的 问题仍然没有答案。我们的长期目标是了解 分子详细的AP-1蛋白的正常功能，以及如何 这种转录因子的失调有助于 癌症。为了实现这一目标，我们提出了具体目标，以解决 以下问题：l）决定能力的蛋白质是什么？ 来激活转录Fos家族蛋白含有一个 转化所需的羧基末端活化结构域。 我们建议进行突变分析，以确定关键的 该结构域的功能所需的残基和二级结构。 这将导致识别与此相互作用的蛋白质的策略 域，并通过这样做来调节其功能。2)君是什么角色 Ras蛋白转化的蛋白质？假设Jun蛋白质 作为细胞转化反应的关键介质， 拉斯我们建议用细胞从遗传学上检验这一假设 在c-Jun基因座含有无效突变。3)什么是功能 AP-1转换所需的域？我们将使用AP-1蛋白 用改变的二聚化特异性来确定分子和 AP-1蛋白转化所需的生物化学功能。在 此外，我们还将讨论AP-1转化的非AP-1决定因素 proteins.

The Fos and Jun gene families encode a series of proteins that are components of the transcription factor AP-1. The oncogenic potential of this transcription factor is exemplified by the fact that both gene families were originally identified by their presence in the genomes of tumorigenic retroviruses. The Fos-Jun complex is a downstream component of a signal transduction pathway that includes the oncogenic tyrosine kinases and ras oncogenes, and AP-1 activity is induced by events that activate tyrosine kinase or ras activity. Therefore, it seems likely that an understanding of the molecular mechanisms involved in neoplastic transformation by AP-l proteins will also help clarify the events that underlie malignant transformation by these other oncoproteins. Although progress in understanding the molecular mechanisms involved in tumor formation by Fos and Jun proteins has been achieved, several critical questions remain unanswered. Our long term goal is to understand in molecular detail the normal functions of AP-l proteins and how deregulation of this transcription factor contributes to the development of cancer. To reach this goal, we propose specific aims to address the following questions: l) what are the proteins that determine the ability of Fos proteins to activate transcription? Fos family proteins contain a carboxyl-terminal activation domain that is required for transformation. We propose to carry out a mutational analysis to identify critical residues and secondary structures required for function of this domain. This will lead to strategies to identify proteins that interact with this domain and by doing so modulate its function. 2) What is the role of Jun proteins in transformation by Ras proteins? Jun proteins are hypothesized to function as critical mediators of the cellular transforming response to ras. We propose to test this hypothesis genetically, using cells containing null mutations at the c-Jun locus. 3) What are the functional domains required for transformation by AP-1? We will use AP-l proteins with altered dimerization specificity to determine the molecular and biochemical functions required for transformation by AP-l proteins. In addition, we will address non-AP-l determinants of transformation by AP-l proteins.