MOLECULAR MECHANISMS OF TRANSFORMATION BY AP 1 PROTEINS

Fos和Jun基因家族编码一系列蛋白质，这些蛋白质 转录因子AP-1的组成成分。卵巢癌的致癌潜力 这种转录因子的例证是这两个基因 家族最初是通过它们在人类基因组中的存在来识别的 致瘤逆转录病毒。Fos-Jun综合体是 包括致癌酪氨酸激酶在内的信号转导途径 和ras癌基因，AP-1活性由激活的事件诱导 酪氨酸激酶或ras活性。因此，看起来很可能是一个 对肿瘤分子机制的认识 AP-L蛋白的转化也将有助于阐明 这些其他癌蛋白的恶性转化是其基础。虽然 肿瘤分子机制的研究进展 已经实现了Fos和Jun蛋白的形成，几个关键的 问题仍然没有得到回答。我们的长期目标是了解 AP-L蛋白的正常功能及其机制的分子细节 这种转录因子的解除调控有助于发育。 癌症的威胁。为了达到这一目标，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 激活转录的Fos蛋白？Fos家族蛋白包含一个 转化所需的羧基末端激活域。 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)Jun的角色是什么 RAS蛋白转化中的蛋白质？Jun蛋白是假想的 作为细胞转化反应的关键介质发挥作用 拉斯。我们建议用细胞从基因上检验这一假说 在c-jun基因座包含零突变。3)功能有哪些 AP-1转换所需的结构域？我们将使用AP-L蛋白 用改变的二聚专一性来确定分子和 AP-L蛋白转化所需的生化功能。在……里面 此外，我们将解决非AP-L的转型决定因素由AP-L 蛋白质。

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.