MOLECULAR MECHANISMS OF TRANSFORMATION BY AP-1 PROTEINS

描述：（改编自研究者摘要） 分子、遗传和生化特征已经证明 转录因子AP-1由二聚体组成， Fos和Jun蛋白的复合物，调节细胞对 多种细胞外刺激AP-1参与了 细胞从正常到恶性生长至少在两个不同的情况下。 首先，Fos和Jun家族的基因可以作为主要靶标 突变激活，如在Fos和Jun的情况下， 致癌逆转录病毒此外，AP-1蛋白可以作为 几种不同细胞质转化的效应子 癌蛋白，其中许多是突变激活的常见靶点 在人类癌症中。除了发挥调解作用外 他们通过遗传分析表明，AP-1蛋白 一般来说，特别是c-Jun，在两个方面发挥着重要作用 细胞过程可能与影响 致癌变化：在成纤维细胞中，正常细胞需要c-Jun 细胞周期的进展，并保护细胞免于凋亡， 不同的凋亡刺激，U/V照射和细胞因子TNF。 他们的长期目标是从分子上详细了解正常的 AP-1蛋白的功能以及这种转录的失调 这一因素有助于癌症的发展。为了达到这个目标， 他们提出了解决以下问题的实验：1）角色 FosB蛋白（和一般的Fos蛋白）的磷酸化是否起作用 在调节转录激活和肿瘤 转化？2)什么是介导磷酸化的激酶 功能重要的网站，它们是如何管理的？3)是什么 c-Jun、JNK和JNK/cJun相互作用在控制 肿瘤转化、细胞增殖和凋亡？4)怎么样 调节细胞周期蛋白D1启动子的AP-1反应性， 不是由激活AP-1的抗增殖刺激物诱导的， 作为U/V辐射？他们提出了一系列的遗传，生化， 细胞生物学实验来解决这些问题。的答案 问题将增加我们对分子基础的理解， 转化为AP-1。

DESCRIPTION: (adapted from the investigator's abstract) Molecular, genetic, and biochemical characterization has demonstrated that the transcription factor AP-1, which is composed of dimeric complexes of Fos and Jun proteins, regulates cellular responses to diverse extracellular stimuli. AP-1 participates in the conversion of cells from normal to malignant growth in at least two separate contexts. First, genes of the Fos and Jun family can serve as the primary targets of mutational activation, as in the case of Fos and Jun containing oncogenic retroviruses. In addition, AP-1 proteins can function as effectors of transformation by several different cytoplasmic oncoproteins, many of which are common targets of mutational activation in human cancers. In addition to playing a role in mediating transformation, they have shown by genetic analysis that AP-1 proteins in general, and c-Jun in particular, play important roles in two cellular processes that may be related to the ability to effect oncogenic changes: in fibroblasts, c-Jun is required for normal cell cycle progression and protects cells from apoptosis in response to two different apoptotic stimuli, U/V irradiation and the cytokine TNF. Their long term goal is to understand in molecular detail the normal functions of AP-1 proteins and how deregulation of this transcription factor contributes to the development of cancer. To reach this goal, they propose experiments to address the following questions: 1) role does phosphorylation of FosB protein (and Fos proteins in general) play in the regulation of transcriptional activation and neoplastic transformation? 2) What are the kinases that mediate phosphorylation at functionally important sites, and how are they regulated? 3) What is the role of c-Jun, JNK, and the JNK/cJun interaction in the control of neoplastic transformation, cell proliferation, and apoptosis? 4) How is the AP-1 responsiveness of the cyclin D1 promoter regulated so that it is not induced by anti-proliferative stimuli that activate AP-1, such as U/V irradiation? They propose a series of genetic, biochemical, and cell biologic experiments to address these issues. The answers to these questions will increase our understanding of the molecular basis of transformation by AP-1.