CYTOCHROME P-450 GENE STRUCTURE AND REGULATION

PAH诱导的P-450负责代谢 致癌物质，以及各种各样的内源性和 外源化合物 这些化合物的代谢可以发生 通过有助于其解毒的途径，或通过 将它们激活为高度致癌形式的途径。 是 我认为解毒和激活之间的平衡是 对化学致癌过程至关重要， 不同个体之间的差异，在特定的P- 450酶活性可能会显著影响这种平衡。 这反过来又会影响个体的易感性 特定形式的癌症。 这种差异的根源在于 酶活性可能存在于结构基因中， 编码P-450酶或在调控基因，控制 P-450基因家族的特定成员的表达。 深入 关于P-450的结构和规则的知识 结构基因和调控基因是决定 这些基因及其基因产物的实际重要性 确定癌症易感性。 本研究的目的 该计划旨在提供这些基本信息。 具体 目标如下： 1. 多种顺式作用序列响应于不同的反式- 控制P-450 c转录的作用因子，和 可能是P-450 d基因。 我们将使用DNA介导的基因转移， 表征的顺式作用转录调控序列，和 用于识别和表征DNA结合的映射技术 与这些相互作用的蛋白质（可能在功能上具有调节作用） 序列的 我们将纯化选定的DNA结合蛋白， 对它们进行生物化学表征，克隆对应于 编码这些因子的mRNAs，并研究这些因子的调控。 mRNA。 2. 多种转录后调控机制控制 将研究P-450 c和P-450 d mRNA水平： P-450 mRNA、mRNA前体和mRNA降解产物将被 分析;控制转录后事件的mRNA序列 将通过DNA介导的基因转移实验定位; 介导转录后过程的蛋白质将被 生物化学研究。 3. 实现上述目标将发展分子- 基因工具，将有助于评估的作用，P- 450年代的致癌作用，也用于确定分子 个体间易感性差异的基础 特定形式的癌症。

The PAH-inducible P-450 are responsible for the metabolism of carcinogens, as well aS a wide variety of both endogenous and exogenous compounds. The metabolism of these compounds can occur via pathways that contribute to their detoxification, or via pathways that activate them to highly cArcinogenic forms. It is thought that the balance between detoxification and activation is crucial to the process of chemicAl carcinogenesis and that differences between individuals in the expression of specific P- 450 enzymatic activities may substantially influence this balance. This will, in turn, influence the susceptibility of the individual to specific forms of cancer. The source of this difference in enzymatic activities could reside in either the structural gene encoding P-450 enzymes or in the regulatory genes that control the expression of specific members of the P-450 gene family. In-depth knowledge regarding the structure and regulation of the P-450 structural genes and regulatory genes is required to determine the actual importance of these genes and their gene products in determining cancer susceptibility. The objective of this research program is to provide this basic information. The specific objectives are as follows: 1. A manifold of cis-acting sequences respond to different trans- acting factors to control the transcription of the P-450c, and probably, P-450d genes. We will use DNA-mediated gene transfer to characterized cis-acting transcriptional regulatory sequences, and mapping techniques to identify and characterize the DNA binding proteins (probably regulatory in function) that interact with these sequences. We will purify selected DNA binding proteins, characterize them biochemically, clone cDNAs corresponding to the mRNAs encoding these factors and study the regulation of these mRNAs. 2. Multiple post-transcription regulatory mechanisms controlling P-450c and P-450d mRNA levels will be studied: the structures of P-450 mRNAs, mRNA precursors and mRNA degradation products will be analyzed; mRNA sequences controlling post-transcriptional events will be located by DNA-mediated gene transfer experiments; an proteins that mediate post-transcriptional processes will be studied biochemically. 3. Accomplishing the above objectives will develop molecular- genetic tools that will be useful for assessing the role of the P- 450s in carcinogenesis and also, for determining the molecular basis of the variations among individuals in their susceptibility to specific forms of cancer.